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1

Polymicrobial Sepsis Enhances Clearance of Apoptotic Immune Cells by Splenic Macrophages  

PubMed Central

Background Macrophage phagocytosis of apoptotic cells induces an anti-inflammatory macrophage phenotype. Immune cell apoptosis is widespread in sepsis; however, it is unknown whether sepsis alters the capacity of macrophages to clear this expanded population. We hypothesize that sepsis will enhance splenic macrophage phagocytosis of apoptotic immune cells, potentially contributing to immunosuppression. Methods Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP). Apoptosis was induced in mouse thymocytes by dexamethasone incubation. At multiple time points following CLP/sham, splenic and peritoneal macrophages were isolated, plated on glass coverslips, co-incubated with apoptotic thymocytes, fixed, and the coverslips were then Giemsa stained. Splenic macrophages were also isolated 48 hours after CLP/sham, stained with the red fluorescent dye PKH26, co-incubated with green fluorescent dye CFSE-stained apoptotic thymocytes and then coverslips were fixed and counterstained with DAPI. The macrophage phagocytic index (PI) was calculated for both staining methods. Results The PI of CLP splenic macrophages was significantly higher than sham by 24 hours, and this difference was sustained through 48 hours. Conclusions Studies suggest that apoptotic cell clearance leads to an anti-inflammatory macrophage condition, which together with our findings in septic macrophages, may point at a process that contributes to septic immune suppression. PMID:17689693

Swan, Ryan; Chung, Chun-Shiang; Albina, Jorge; Cioffi, William; Perl, Mario; Ayala, Alfred

2007-01-01

2

Innate immune responses of porcine macrophage cell line (Cdelts2+) to virus-associated virulence determinants  

Technology Transfer Automated Retrieval System (TEKTRAN)

The goal of this study was to define the changes in the expression of immune genes in response to virus-associated virulence determinants. We stimulated a monocyte-derived porcine macrophage cell line (Cdelta2+) for 3 and 24h with Imiquimod, Poly IC and Poly IC with Lyovec. Cell lysates were process...

3

Monocytes and Macrophages Regulate Immunity through Dynamic Networks of Survival and Cell Death  

PubMed Central

Monocytes and macrophages are central cells of the innate immune system, responsible for defending against diverse pathogens. While they originate from a common myeloid precursor and share functions in innate immunity, each has a very distinct life span finely tuned by the apoptotic caspases. Normally, circulating monocytes are short-lived and undergo spontaneous apoptosis on a daily basis. Macrophages, however, have a longer life span. In chronic inflammatory diseases and, as recently recognized, in the tumor microenvironment, the inhibition of the apoptotic program promotes monocyte survival contributing to the accumulation of macrophages and the persistence of an inflammatory milieu. A complex network of differentiation factors and inflammatory stimuli determine monocyte/macrophage life span by blocking the apoptotic pathway and activating a myriad of survival pathways. Our understanding of apoptosis has flourished over the last decade, and its relevance in the regulation of the immune system is now indisputable. Nevertheless, how the complicated networks of survival and apoptotic regulators are integrated to determine cellular life span remains elusive. This review summarizes the contribution of the caspases and their regulators in monocyte/macrophage cell fate and discusses how these molecules orchestrate the initiation, maintenance, and resolution of inflammation. More provocatively, we discuss possible strategies to control inflammation by manipulating leukocyte life span. PMID:20375558

Parihar, Arti; Eubank, Timothy D.; Doseff, Andrea I.

2010-01-01

4

In vitro immune toxicity of polybrominated diphenyl ethers on murine peritoneal macrophages: Apoptosis and immune cell dysfunction.  

PubMed

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants and are often detected in the environment, wildlife, and humans, presenting potential threats to ecosystem and human health. PBDEs can cause neurotoxicity, hepatotoxicity, and endocrine disruption. However, data on PBDE immunotoxicity are limited, and the toxicity mechanisms remain largely unknown. Both immune cell death and dysfunction can modulate the responses of the immune system. This study examined the toxic effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and decabromodiphenyl ether (BDE-209) on the immune system by using peritoneal macrophages as the model. The macrophages were exposed to PBDEs, and cell death was determined through flow cytometry and immunochemical blot. The results showed that after 24h of exposure, BDE-47 (>5?M) and BDE-209 (>20?M) induced cell apoptosis, increased intracellular reactive oxygen species (ROS) formation and depleted glutathione. BDE-47 was more potent than BDE-209; the cytotoxic concentrations for BDE-47 and BDE-209 were determined to be 5?M and 20?M, respectively, during 24h of exposure. However, pretreatment with n-acetyl-l-cysteine (ROS scavenger) partially reversed the cytotoxic effects. Further gene expression analyses on Caspase-3,-8,-9, TNFR1, and Bax revealed that both intrinsic and extrinsic apoptotic pathways were activated. More importantly, non-cytotoxic concentrations BDE-47 (<2?M) and BDE-209 (<10?M) could impair macrophage accessory cell function in a concentration-dependent manner, but no effects were observed on phagocytic responses. These revealed effects of PBDEs on macrophages may shed light on the toxicity mechanisms of PBDEs and suggest the necessity of evaluating cellular functionality during the risk assessment of PBDE immunotoxicity. PMID:25462306

Lv, Qi-Yan; Wan, Bin; Guo, Liang-Hong; Zhao, Lixia; Yang, Yu

2015-02-01

5

Uptake and handling of iron from transferrin, lactoferrin and immune complexes by a macrophage cell line.  

PubMed Central

The murine macrophage-like cell line P388D1 has been used as a model to investigate whether iron acquired simultaneously from different sources (transferrin, lactoferrin, and ovotransferrin-anti-ovotransferrin immune complexes) is handled in the same way. P388D1 cells bound both lactoferrin and transferrin, but over a 6 h incubation period only the latter actually donated iron to the cells. When the cells were incubated with [55Fe]transferrin and [59Fe]ovotransferrin-anti-ovotransferrin immune complexes iron was acquired from both sources. However, there was a difference in the intracellular distribution of the two isotopes, proportionally more 55Fe entering haem compounds and less entering ferritin. When the cells were precultured in a low-iron serum-free medium almost no transferrin-iron was incorporated into ferritin, whereas the proportion of immune complex-derived iron incorporated into ferritin was unchanged. Lactoferrin enhanced the rate of cellular proliferation, as measured by [3H]thymidine incorporation, despite its inability to donate iron to the cells, suggesting a stimulatory effect independent of iron donation. In contrast immune complexes inhibited cell proliferation. These findings indicate that iron acquired from transferrin and iron acquired by scavenging mechanisms are handled differently, and suggest that more than one intracellular iron transit pool may exist. PMID:3421902

Oria, R; Alvarez-Hernández, X; Licéaga, J; Brock, J H

1988-01-01

6

Microparticles released by Listeria monocytogenes-infected macrophages are required for dendritic cell-elicited protective immunity  

PubMed Central

Interplay between macrophages and dendritic cells in the processing and presentation of bacterial antigens for T-cell immune responses remains poorly understood. Using a Listeria monocytogenes (Lm) infection model, we demonstrate that dendritic cells (DCs) require the support of macrophages to elicit protective immunity against Lm infection. DCs themselves were inefficient at taking up Lm but capable of taking up microparticles (MPs) released by Lm-infected macrophages. These MPs transferred Lm antigens to DCs, allowing DCs to present Lm antigen to effector T cells. MP-mediated Lm antigen transfer required MHC class I participation, since MHC class I deficiency in macrophages resulted in a significant reduction of T-cell activation. Moreover, the vaccination of mice with MPs from Lm-infected macrophages produced strong protective immunity against Lm infection. We here identify an intrinsic antigen transfer program between macrophages and DCs during Lm infection, and emphasize that macrophages also play an essential role in DC-elicited Lm-specific T-cell responses. PMID:23064105

Zhang, Yi; Zhang, Ruihua; Zhang, Huafeng; Liu, Jing; Yang, Zhuoshun; Xu, Pingwei; Cai, Wenqian; Lu, Geming; Cui, Miao; Schwendener, Reto A; Shi, Huang-Zhong; Xiong, Huabao; Huang, Bo

2012-01-01

7

A Novel Polysaccharide in Insects Activates the Innate Immune System in Mouse Macrophage RAW264 Cells  

PubMed Central

A novel water-soluble polysaccharide was identified in the pupae of the melon fly (Bactrocera cucurbitae) as a molecule that activates the mammalian innate immune response. We attempted to purify this innate immune activator using nitric oxide (NO) production in mouse RAW264 macrophages as an indicator of immunostimulatory activity. A novel acidic polysaccharide was identified, which we named “dipterose”, with a molecular weight of 1.01×106 and comprising nine monosaccharides. Dipterose was synthesized in the melon fly itself at the pupal stage. The NO-producing activity of dipterose was approximately equal to that of lipopolysaccharide, a potent immunostimulator. Inhibition of Toll-like receptor 4 (TLR4) led to the suppression of NO production by dipterose. Furthermore, dipterose induced the expression of proinflammatory cytokines and interferon ? (IFN?) and promoted the activation of nuclear factor kappa B (NF-?B) in macrophages, indicating that it stimulates the induction of various cytokines in RAW264 cells via the TLR4 signaling pathway. Our results thus suggest that dipterose activates the innate immune response against various pathogenic microorganisms and viral infections. This is the first identification of an innate immune-activating polysaccharide from an animal. PMID:25490773

Ohta, Takashi; Ido, Atsushi; Kusano, Kie; Miura, Chiemi; Miura, Takeshi

2014-01-01

8

A Novel Polysaccharide in Insects Activates the Innate Immune System in Mouse Macrophage RAW264 Cells.  

PubMed

A novel water-soluble polysaccharide was identified in the pupae of the melon fly (Bactrocera cucurbitae) as a molecule that activates the mammalian innate immune response. We attempted to purify this innate immune activator using nitric oxide (NO) production in mouse RAW264 macrophages as an indicator of immunostimulatory activity. A novel acidic polysaccharide was identified, which we named "dipterose", with a molecular weight of 1.01×106 and comprising nine monosaccharides. Dipterose was synthesized in the melon fly itself at the pupal stage. The NO-producing activity of dipterose was approximately equal to that of lipopolysaccharide, a potent immunostimulator. Inhibition of Toll-like receptor 4 (TLR4) led to the suppression of NO production by dipterose. Furthermore, dipterose induced the expression of proinflammatory cytokines and interferon ? (IFN?) and promoted the activation of nuclear factor kappa B (NF-?B) in macrophages, indicating that it stimulates the induction of various cytokines in RAW264 cells via the TLR4 signaling pathway. Our results thus suggest that dipterose activates the innate immune response against various pathogenic microorganisms and viral infections. This is the first identification of an innate immune-activating polysaccharide from an animal. PMID:25490773

Ohta, Takashi; Ido, Atsushi; Kusano, Kie; Miura, Chiemi; Miura, Takeshi

2014-01-01

9

Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages  

PubMed Central

There is limited information about the role of blood-brain barrier (BBB) endothelial cells (ECs) in the central nervous system (CNS) and their innate immunity against HIV. We examined whether brain ECs can be immunologically activated to produce antiviral factors that inhibit HIV replication in macrophages. Human brain microvascular ECs expressed functional toll-like receptor 3 (TLR3) that could be activated by polyinosinic-polycytidylic acid (PolyI:C), resulting in the induction of endogenous interferon-? (IFN-?) and IFN-?. The TLR3 activation of ECs also induced the phosphorylation of interferon regulatory transcription factor 3 (IRF3) and IRF7, the key regulators of IFN signaling pathway. When supernatant (SN) of PolyI:C-activated EC cultures was applied to infected macrophage cultures, HIV replication was significantly suppressed. This SN action of ECs on HIV was mediated through both IFN-? and IFN-? because antibodies to their receptors could neutralize the SN-mediated anti-HIV effect. The role of IFNs in EC-mediated anti-HIV activity is further supported by the observation that treatment with SN from EC cultures induced the expression of IFN-stimulated genes (ISGs: ISG56, OAS-1, and MxA) in macrophages. These observations indicate that brain microvascular ECs may be a key regulatory bystander, playing a crucial role in the BBB innate immunity against HIV infection. PMID:23401273

Li, Jieliang; Wang, Yizhong; Wang, Xu; Ye, Li; Zhou, Yu; Persidsky, Yuri

2013-01-01

10

The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response  

PubMed Central

The complicated interactions between Leishmania and the host antigen-presenting cells (APCs) have fundamental effects on the final outcome of the disease. Two major APCs, macrophages and dendritic cells (DCs), play critical roles in mediating resistance and susceptibility during Leishmania infection. Macrophages are the primary resident cell for Leishmania: they phagocytose and permit parasite proliferation. However, these cells are also the major effector cells to eliminate infection. The effective clearance of parasites by macrophages depends on activation of appropriate immune response, which is usually initiated by DCs. Here, we review the early interaction of APCs with Leishmania parasites and how these interactions profoundly impact on the ensuing adaptive immune response. We also discuss how the current knowledge will allow further refinement of our understanding of the interplay between Leishmania and its hosts that leads to resistance or susceptibility. PMID:22919674

Liu, Dong; Uzonna, Jude E.

2012-01-01

11

Vaccination with Irradiated Autologous Melanoma Cells Engineered to Secrete Human Granulocyte--Macrophage Colony-Stimulating Factor Generates Potent Antitumor Immunity in Patients with Metastatic Melanoma  

Microsoft Academic Search

We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte--macrophage colony-stimulating factor in patients with metastatic melanoma. Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of

Robert Soiffer; Thomas Lynch; Martin Mihm; Ken Jung; Catherine Rhuda; Jan C. Schmollinger; F. Stephen Hodi; Laura Liebster; Prudence Lam; Steven Mentzer; Samuel Singer; Kenneth K. Tanabe; A. Benedict Cosimi; Rosemary Duda; Arthur Sober; Atul Bhan; John Daley; Donna Neuberg; Gordon Parry; Joseph Rokovich; Laurie Richards; Jan Drayer; Anton Berns; Shirley Clift; Lawrence K. Cohen; Richard C. Mulligan; Glenn Dranoff

1998-01-01

12

Macrophages and Dendritic Cells as Actors in the Immune Reaction of Classical Hodgkin Lymphoma  

PubMed Central

Background The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (M?) and dendritic cells (DC). Methods M? and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, M? stimulated with GM-CSF (M?GM-CSF, pro-inflammatory M?-1-model) or M-CSF (M?M-CSF, immunomodulatory M?-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or M? polarization were investigated by flow cytometry. Furthermore, the impact of DC or M? on cHL cell proliferation was analyzed by BrdU/CFSE assay. Results In cHL tissues mature myeloid (m)DC and M? predominated. High numbers of CD83+ mDC and low numbers of CD163+ M? were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory M? phenotype were promoted by SN derived from cHL cell lines. TNF? neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory M? inhibited the proliferation of cHL cells. Conclusion Adopting an immunomodulatory phenotype is a potential mechanism for how M? promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunity. PMID:25470820

Tudor, Christiane Silke; Bruns, Heiko; Daniel, Christoph; Distel, Luitpold Valentin; Hartmann, Arndt; Gerbitz, Armin; Buettner, Maike Julia

2014-01-01

13

Macrophages in homeostatic immune function  

PubMed Central

Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders. PMID:24847274

Jantsch, Jonathan; Binger, Katrina J.; Müller, Dominik N.; Titze, Jens

2014-01-01

14

Porcine macrophage Cdelta2+ and Cdelta2- cell lines support influenza virus infection and replication and Cdelta2+ cells mount innate immune responses to influenza virus infection  

Technology Transfer Automated Retrieval System (TEKTRAN)

Respiratory epithelial cells are the first cells which are infected with influenza virus and these cells play a major role in influenza pathogenesis. However, many studies have shown that alveolar macrophages also play a very important role in the pathogenesis and immunity to influenza infection. Un...

15

Inhibition of immune opsonin-independent phagocytosis by antibody to a pulmonary macrophage cell surface antigen  

SciTech Connect

Unlike other hamster phagoycytes, hamster pulmonary macrophages (PM) avidly ingest albumin-coated latex particles in the absence of serum. They also possess a highly specific cell surface antigen. To evaluate the relationship between these two characteristics, PM were incubated with mouse monoclonal antibody directed against the PM antigen. After unbound antibody was removed, the amount of bound antibody and the phagocytic capability of PM were measured by flow cytometry and fluorescence microscopy. Maximum antibody binding produced a 25% inhibition of ingestion. Particle attachment was not affected. This effect was antigen specific, since neither a nonspecific mouse myeloma protein of the same subclass nor a mouse antibody that bound to another hamster surface antigen had any effect on binding or ingestion. If antigen-specific F(ab')/sub 2/ fragments were introduced both before and during the period of phagocytosis, the inhibition of particle ingestion approached 100%. Particle binding increased at low F(ab')/sub 2/ concentrations but declined at higher concentrations. Because calcium may play a role in the ingestion process, the effect of antibody on /sup 45/Ca uptake was evaluated. It was observed that antigen-specific F(ab')/sub 2/ fragments stimulated /sup 45/Ca uptake, whereas control antibodies did not. These results suggest that the antigen reacting with the anti-hamster PM monoclonal antibody is involved in immune opsonin-independent phagocytosis and that calcium participates in this phagocytic process.

Parod, R.J.; Godleski, J.J.; Brain J.D.

1986-03-15

16

Immune specific production of interferon by human T cells in combined macrophage-lymphocyte cultures in response to Herpes simplex antigen.  

PubMed

Human peripheral blood lymphocytes, highly enriched for T cells, were obtained by passing gravity-sedimented leukocytes through nylon wool columns. The eluted cells were cultured with autologous macrophages and the mixture was studied for its capacity to produce interferon in vitro in response to stimulation with herpes simplex virus antigen. The interferon produced by the combined macrophage-lymphocyte cultures was shown to depend upon the presence of T cells; elimination of these cells by treatment with an anti-T cell serum plus complement greatly diminished the amount of interferon produced. The memory for the immune-specific release of interferon also appeared to be carried by the T lymphocytes rather than the glass-adherent macrophages. Furthermore, the results suggest that under our conditions of culture immune-specific interferon originates from T cells. PMID:46881

Valle, M J; Bobrove, A M; Strober, S; Merigan, T C

1975-01-01

17

Cooperativity Between CD8+ T Cells, Non-Neutralizing Antibodies, and Alveolar Macrophages Is Important for Heterosubtypic Influenza Virus Immunity  

PubMed Central

Seasonal epidemics of influenza virus result in ?36,000 deaths annually in the United States. Current vaccines against influenza virus elicit an antibody response specific for the envelope glycoproteins. However, high mutation rates result in the emergence of new viral serotypes, which elude neutralization by preexisting antibodies. T lymphocytes have been reported to be capable of mediating heterosubtypic protection through recognition of internal, more conserved, influenza virus proteins. Here, we demonstrate using a recombinant influenza virus expressing the LCMV GP33-41 epitope that influenza virus-specific CD8+ T cells and virus-specific non-neutralizing antibodies each are relatively ineffective at conferring heterosubtypic protective immunity alone. However, when combined virus-specific CD8 T cells and non-neutralizing antibodies cooperatively elicit robust protective immunity. This synergistic improvement in protective immunity is dependent, at least in part, on alveolar macrophages and/or other lung phagocytes. Overall, our studies suggest that an influenza vaccine capable of eliciting both CD8+ T cells and antibodies specific for highly conserved influenza proteins may be able to provide heterosubtypic protection in humans, and act as the basis for a potential “universal” vaccine. PMID:23516357

Laidlaw, Brian J.; Decman, Vilma; Ali, Mohammed-Alkhatim A.; Abt, Michael C.; Wolf, Amaya I.; Monticelli, Laurel A.; Mozdzanowska, Krystyna; Angelosanto, Jill M.; Artis, David; Erikson, Jan; Wherry, E. John

2013-01-01

18

Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils  

Microsoft Academic Search

Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired

Stephen J Galli; Niels Borregaard; Thomas A Wynn

2011-01-01

19

Macrophages are involved in hexachlorobenzene-induced adverse immune effects  

SciTech Connect

Hexachlorobenzene (HCB) is a persistent environmental pollutant that causes adverse immune effects in man and rat. The Brown Norway (BN) rat is very susceptible to HCB-induced immunopathology and oral exposure causes inflammatory skin and lung lesions, splenomegaly, lymph node (LN) enlargement, and increased serum levels of IgE and anti-ssDNA IgM. T cells play an important role but do not account for all adverse effects induced by HCB. Macrophages are probably also important and the relationship between macrophages and T cells was further investigated. To eliminate macrophages clodronate-liposomes were used. Furthermore, a kinetic study was performed to obtain insight in the early phase of the HCB-induced immune response. Also, experiments were performed to detect specific memory T cells. Therefore, an adoptive transfer study was performed. Our results indicate that macrophages are indeed involved in HCB-induced skin lesions, lung eosinophilia, and elevation of IgM against ssDNA. Kinetics showed that both skin and lung lesions appeared early after exposure. Moreover, immune effects could not be adaptively transferred. Thus, both macrophages and T cells are involved in HCB-induced immune effects but HCB exposure does not lead to specific T cell sensitization. Presumably, HCB exposure induces macrophage activation, thereby generating adjuvant signals that polyclonally stimulate T cells. Together, these events may lead to the observed immunopathology in BN rats.

Ezendam, Janine [National Institute for Public Health and the Environment, Laboratory for Toxicology, Pathology and Genetics, Bilthoven, PO Box 1 3720 BA (Netherlands)]. E-mail: Janine.Ezendam@rivm.nl; Kosterman, Kevin [Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, PO Box 80.176, 3508 TD Utrecht (Netherlands); Spijkerboer, Henneke [Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, PO Box 80.176, 3508 TD Utrecht (Netherlands); Bleumink, Rob [Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, PO Box 80.176, 3508 TD Utrecht (Netherlands); Hassing, Ine [Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, PO Box 80.176, 3508 TD Utrecht (Netherlands); Rooijen, Nico van [Faculty of Medicine, Department of Molecular Cell Biology, Free University, PO Box 7057, 1007 MB Amsterdam (Netherlands); Vos, Joseph G. [National Institute for Public Health and the Environment, Laboratory for Toxicology, Pathology and Genetics, Bilthoven, PO Box 1 3720 BA (Netherlands); Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, PO Box 80.150, 3508 TD Utrecht (Netherlands); Pieters, Raymond [Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, PO Box 80.176, 3508 TD Utrecht (Netherlands)

2005-11-15

20

Autocrine IL-10 induces hallmarks of alternative activation in macrophages and suppresses anti-tuberculosis effector mechanisms without compromising T cell immunity1  

PubMed Central

Elevated IL-10 has been implicated in reactivation tuberculosis (TB). Since macrophages rather than T cells were reported to be the major source of IL-10 in TB, we analyzed the consequences of a macrophage-specific overexpression of IL-10 in transgenic mice (macIL-10-transgenic) after aerosol infection with Mycobacterium tuberculosis (Mtb). MacIL-10-transgenic mice were more susceptible to chronic Mtb infection than non-transgenic littermates, exhibiting higher bacterial loads in the lung after 12 weeks of infection and dying significantly earlier than controls. The differentiation, recruitment and activation of TH1 cells as well as the induction of IFN-gamma-dependent effector genes against Mtb were not affected by macrophage-derived IL-10. However, microarray analysis of pulmonary gene expression revealed patterns characteristic of alternative macrophage activation that were overrepresented in Mtb-infected macIL-10-transgenic mice. Importantly, arginase-1 gene expression and activity were strikingly enhanced in transgenic mice accompanied by a reduced production of reactive nitrogen intermediates. Moreover, IL-10-dependent arginase-1 induction diminished anti-mycobacterial effector mechanisms in macrophages. Together, macrophage-derived IL-10 triggers aspects of alternative macrophage activation and promotes Mtb recrudescence independent of overt effects on anti-TB T cell immunity. PMID:19561100

Schreiber, Tanja; Ehlers, Stefan; Heitmann, Lisa; Rausch, Alexandra; Mages, Jörg; Murray, Peter J.; Lang, Roland; Hölscher, Christoph

2009-01-01

21

Do macrophage innate immune receptors enhance atherogenesis?  

PubMed

Macrophages play a central role in both innate immunity to infection and atherosclerosis. Castrillo and colleagues report that selected microbial agonists for Toll-like receptors strongly inhibit LXR-mediated cholesterol efflux from macrophages. TLR-LXR crosstalk could explain how nonspecific microbial infections promote atherogenesis. PMID:14602065

Gordon, Siamon

2003-11-01

22

The Prognostic Implications of Macrophages Expressing Proliferating Cell Nuclear Antigen in Breast Cancer Depend on Immune Context  

PubMed Central

Tumor associated macrophages (TAMs) are recruited from the circulation to the tumor site, and can undergo a spectrum of phenotypic changes, with two contrasting activation states described in the literature: the M1 and M2 phenotypes. We previously identified a population of TAMs that express proliferating cell nuclear antigen (PCNA) and are associated with high grade, hormone receptor negative breast cancers and poor outcomes. In the present exploratory study we again found that high PCNA+ TAM counts in pre-treatment tumor biopsies (102 invasive breast cancer cases from the I-SPY 1 Trial, a prospective neoadjuvant trial with serial core biopsies and gene array data) were associated with high grade, hormone receptor negativity, and decreased recurrence free survival. We explored the association of these PCNA+ TAMs with the expression of M1 and M2 related genes and, contrary to expectation, observed that high PCNA+ TAM levels were associated with more M1- than M2-related genes. An immune gene signature, derived from cytotoxic T cell and MHC Class II genes (Tc/ClassII), was developed and we found that high PCNA+ TAM counts, in the context of a low Tc/ClassII signature score, were associated with significantly worse recurrence free survival in all cases and in hormone receptor negative only cases. We observed similar results using a gene signature-proxy for PCNA+ TAMs in a larger independent set of 425 neoadjuvant-treated breast cancer cases. The results of this exploratory study indicate that high numbers of PCNA+ TAMs, in the absence of an anti-tumor immune microenvironment (as indicated by a low Tc/ClassII signature score), are associated with poor outcomes in breast cancer patients treated with neoadjuvant chemotherapy. This, along with the observation that PCNA+ TAMs were associated predominantly with M1-related genes, may provide new insights into the role of the immune microenvironment in breast cancer. PMID:24205370

Campbell, Michael J.; Wolf, Denise; Mukhtar, Rita A.; Tandon, Vickram; Yau, Christina; Au, Alfred; Baehner, Frederick; van’t Veer, Laura; Berry, Donald; Esserman, Laura J.

2013-01-01

23

Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections.  

PubMed

Direct mammalian target of rapamycin (Rapa) complex 1 inhibition by short-term low-dose Rapa treatment has recently been shown to improve CD8 T cell immunological memory. Whereas these studies focused on memory development, the impact of low-dose Rapa on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. In this study, we investigated the impact of acute Rapa treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naive cells and the reduced formation of short-lived effector cells. Therefore, more than one cell type required for a protective effector immune response is impaired by Rapa in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of Rapa treatment as means to improve immune memory. PMID:24913978

Goldberg, Emily L; Smithey, Megan J; Lutes, Lydia K; Uhrlaub, Jennifer L; Nikolich-Žugich, Janko

2014-07-15

24

Modulation of macrophage immune responses by Echinacea.  

PubMed

Echinacea preparations are widely used herbal medicines for the prevention and treatment of colds and minor infections. There is little evidence for the individual components in Echinacea that contribute to immune regulatory activity. Activity of an ethanolic Echinacea extract and several constituents, including cichoric acid, have been examined using three in vitro measures of macrophage immune function - NF-kappaB, TNF- alpha and nitric oxide (NO). In cultured macrophages, all components except the monoene alkylamide (AA1) decreased lipopolysaccharide (LPS) stimulated NF-kappaB levels. 0.2 microg/ml cichoric acid and 2.0 microg/mL Echinacea Premium Liquid (EPL) and EPL alkylamide fraction (EPL AA) were found to significantly decrease TNF-alpha production under LPS stimulated conditions in macrophages. In macrophages, only the alkylamide mixture isolated from the ethanolic Echinacea extract decreased LPS stimulated NO production. In this study, the mixture of alkylamides in the Echinacea ethanolic liquid extract did not respond in the same manner in the assays as the individual alkylamides investigated. While cichoric acid has been shown to affect NF-kappaB, TNF-alpha and NO levels, it is unlikely to be relevant in the Echinacea alterations of the immune response in vivo due to its non- bioavailability - i.e. no demonstrated absorption across the intestinal barrier and no detectable levels in plasma. These results demonstrate that Echinacea is an effective modulator of macrophage immune responses in vitro. PMID:18007520

Stevenson, Lesley M; Matthias, Anita; Banbury, Linda; Penman, Kerry G; Bone, Kerry M; Leach, David Leach; Lehmann, Reg P

2005-01-01

25

Alcoholism Causes Alveolar Macrophage Zinc Deficiency and Immune Dysfunction  

PubMed Central

Rationale: Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism. Objectives: We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects. Methods: We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony–stimulating factor receptor; all three of these indices are decreased in experimental models. Measurements and Main Results: Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony–stimulating factor receptor ? subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function. Conclusions: These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals. PMID:23805851

Yeligar, Samantha M.; Elon, Lisa; Brown, Lou Ann; Guidot, David M.

2013-01-01

26

Alum induces innate immune responses through macrophage and mast cell sensors, but these are not required for alum to act as an adjuvant for specific immunity.12  

PubMed Central

To understand more about how the body recognizes alum we characterized the early innate and adaptive responses in mice injected with the adjuvant. Within hours of exposure, alum induces a type 2 innate response characterized by an influx of eosinophils, monocytes, neutrophils, DCs, NK cells and NKT cells. In addition, at least thirteen cytokines and chemokines are produced within 4 hours of injection including IL-1? and IL-5. Optimal production of some of these, including IL-1?, depends upon both macrophages and mast cells, while production of others, such as IL-5, depends on mast cells only, suggesting that both of these cell types can detect alum. Alum induces eosinophil accumulation partly through the production of mast cell derived IL-5 and histamine. Alum greatly enhances priming of endogenous CD4 and CD8 T cells independently of mast cells, macrophages and of eosinophils. In addition, antibody levels and Th2 bias was similar in the absence of these cells. We found that the inflammation induced by alum was unchanged in caspase-1 deficient mice, which cannot produce IL-1?. Furthermore, endogenous CD4 and CD8 T cell responses, antibody responses and the Th2 bias were also not impacted by the absence of caspase-1 or NLRP3. These data suggest that activation of the inflammasome and the type 2 innate response orchestrated by macrophages and mast cells in vivo are not required for alum's adjuvant effects on endogenous T and B cell responses. PMID:19734227

McKee, Amy S.; Munks, Michael W.; MacLeod, Megan K. L.; Fleenor, Courtney J.; Van Rooijen, Nico; Kappler, John W.; Marrack, Philippa

2010-01-01

27

Macrophages as IL-25/IL-33-responsive cells play an important role in the induction of type 2 immunity  

Technology Transfer Automated Retrieval System (TEKTRAN)

Th2 immunity is essential for the host protection against nematode infection, while detrimental in allergic inflammation or asthma. Although many of the details regarding the cellular and molecular events in Th2 immunity have been described, the specific cell types and effector molecules involved i...

28

TLR3 Signaling in Macrophages Is Indispensable for the Protective Immunity of Invariant Natural Killer T Cells against Enterovirus 71 Infection  

PubMed Central

Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients. PMID:25615690

Zhu, Kai; Yang, Juhao; Luo, Kaiming; Yang, Chunhui; Zhang, Na; Xu, Ruifeng; Chen, Jianxia; Jin, Mingfei; Xu, Bin; Guo, Nining; Wang, Jianrong; Chen, Zuolong; Cui, Ying; Zhao, Hui; Wang, Yan; Deng, Chaoyang; Bai, Li; Ge, Baoxue; Qin, Cheng-Feng; Shen, Hao; Yang, Chun-Fu; Leng, Qibin

2015-01-01

29

Mouse macrophage innate immune response to chikungunya virus infection  

PubMed Central

Background Infection with Chikungunya alphavirus (CHIKV) can cause severe arthralgia and chronic arthritis in humans with persistence of the virus in perivascular macrophages of the synovial membrane by mechanisms largely ill-characterized. Findings We herein analysed the innate immune response (cytokine and programmed cell death) of RAW264.7 mouse macrophages following CHIKV infection. We found that the infection was restrained to a small percentage of cells and was not associated with a robust type I IFN innate immune response (IFN-?4 and ISG56). TNF-?, IL-6 and GM-CSF expression were upregulated while IFN-?, IL-1?, IL-2, IL-4, IL-5, IL-10 or IL-17 expression could not be evidenced prior to and after CHIKV exposure. Although CHIKV is known to drive apoptosis in many cell types, we found no canonical signs of programmed cell death (cleaved caspase-3, -9) in infected RAW264.7 cells. Conclusion These data argue for the capacity of CHIKV to infect and drive a specific innate immune response in RAW264.7 macrophage cell which seems to be polarized to assist viral persistence through the control of apoptosis and IFN signalling. PMID:23253140

2012-01-01

30

M1 and M2 macrophages: the chicken and the egg of immunity.  

PubMed

The purpose of this perspective is to describe a critical advance in understanding how immune responses work. Macrophages are required for all animal life: 'Inhibit' type macrophages in all animals (called M1) can rapidly kill pathogens, and are thus the primary host defense, and 'Heal' type macrophages (M2) routinely repair and maintain tissue integrity. Macrophages perform these activities in all animals without T cells, and also in T cell-deficient vertebrates. Although adaptive immunity can amplify macrophage polarization, the long-held notion that macrophages need to be 'activated' or 'alternatively activated' by T cells is incorrect; indeed, immunology has had it backward. M1/M2-type macrophages necessarily direct T cells toward Th1- or Th2-like activities, respectively. That such macrophage-innate activities are the central directing element in immune responses is a dramatic change in understanding how immune systems operate. Most important, this revelation is opening up whole new approaches to immunotherapy. For example, many modern diseases, such as cancer and atherosclerosis, may not display 'foreign' antigens. However, there are clear imbalances in M1/M2-type responses. Correcting such innate imbalances can result in better health. Macrophages are the chicken and the egg of immunity. PMID:25138714

Mills, Charles D; Ley, Klaus

2014-01-01

31

Altered macrophage differentiation and immune dysfunction in tumor development  

PubMed Central

Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response. PMID:17476345

Sica, Antonio; Bronte, Vincenzo

2007-01-01

32

Crude extract of Polygonum cuspidatum stimulates immune responses in normal mice by increasing the percentage of Mac-3-positive cells and enhancing macrophage phagocytic activity and natural killer cell cytotoxicity  

PubMed Central

Polygonum cuspidatum is a natural plant that is used in traditional Chinese herbal medicine. The crude extract of Polygonum cuspidatum (CEPC) has numerous biological effects; however, there is a lack of studies on the effects of CEPC on immune responses in normal mice. The aim of the present study was to determine the in vivo effects of CEPC on immune responses in normal mice. CEPC (0, 50, 100, 150 and 200 mg/kg) was orally administered to BALB/c mice for three weeks, following which blood, liver, and spleen samples were collected. CEPC did not significantly affect the total body weight, or tissue weights of the liver or spleen, as compared with the control mice. CEPC increased the percentages of CD3 (T-cell marker), 11b (monocytes) and Mac-3 (macrophages) positive-cells, and reduced the percentage of CD19-positive cells (B-cell marker), as compared with the control mice. CEPC (100 mg/kg) stimulated macrophage phagocytosis of blood samples but did not affect macrophage phagocytosis in the peritoneum. Activity of the splenic natural killer cells was increased in response to CEPC (50 mg/kg) treatment. Furthermore, CEPC inhibited T- and B-cell proliferation when the cells were stimulated with concanavalin A and lipopolysaccharide, respectively. PMID:25338846

CHUEH, FU-SHIN; LIN, JEN-JYH; LIN, JU-HWA; WENG, SHU-WEN; HUANG, YI-PING; CHUNG, JING-GUNG

2015-01-01

33

Crude extract of Polygonum cuspidatum stimulates immune responses in normal mice by increasing the percentage of Mac-3-positive cells and enhancing macrophage phagocytic activity and natural killer cell cytotoxicity.  

PubMed

Polygonum cuspidatum is a natural plant that is used in traditional Chinese herbal medicine. The crude extract of Polygonum cuspidatum (CEPC) has numerous biological effects; however, there is a lack of studies on the effects of CEPC on immune responses in normal mice. The aim of the present study was to determine the in vivo effects of CEPC on immune responses in normal mice. CEPC (0, 50, 100, 150 and 200 mg/kg) was orally administered to BALB/c mice for three weeks, following which blood, liver, and spleen samples were collected. CEPC did not significantly affect the total body weight, or tissue weights of the liver or spleen, as compared with the control mice. CEPC increased the percentages of CD3 (T-cell marker), 11b (monocytes) and Mac-3 (macrophages) positive-cells, and reduced the percentage of CD19-positive cells (B-cell marker), as compared with the control mice. CEPC (100 mg/kg) stimulated macrophage phagocytosis of blood samples but did not affect macrophage phagocytosis in the peritoneum. Activity of the splenic natural killer cells was increased in response to CEPC (50 mg/kg) treatment. Furthermore, CEPC inhibited T- and B-cell proliferation when the cells were stimulated with concanavalin A and lipopolysaccharide, respectively. PMID:25338846

Chueh, Fu-Shin; Lin, Jen-Jyh; Lin, Ju-Hwa; Weng, Shu-Wen; Huang, Yi-Ping; Chung, Jing-Gung

2015-01-01

34

Maternal immune activation leads to activated inflammatory macrophages in offspring  

PubMed Central

Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg polyinosinic–polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFN-?/LPS. Following stimulation with LPS alone, or the combination of IFN-?/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-?/LPS (p < 0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood. PMID:24566386

Onore, Charity E.; Schwartzer, Jared J.; Careaga, Milo; Bennan, Robert F.; Ashwood, Paul

2015-01-01

35

Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption  

SciTech Connect

Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2?, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions.

Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children's of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Robbins, David J. [Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami (United States); Matalon, Sadis [Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL (United States); Deshane, Jessy S. [Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL (United States); Afaq, Farrukh [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Bickers, David R. [Department of Dermatology, Columbia University Medical Center, New York (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States)

2013-11-01

36

Acquired immunity in experimental murine aspergillosis is mediated by macrophages.  

PubMed Central

A number of studies have substantiated the pivotal role of innate defense mechanisms in protection against invasive aspergillosis. However, experiments demonstrating increased resistance to lethal intravenous (i.v.) infection with Aspergillus fumigatus conidia in cortisone-treated or untreated mice preinfected with a sublethal dose of conidia and protection of turkeys inoculated subcutaneously with a killed A. fumigatus germling vaccine against subsequent aerosol challenge led us to speculate that acquired immunity may also contribute to host defense against Aspergillus infection. Five-week-old male BALB/c mice were inoculated i.v. with 1.0 x 10(4) viable conidia or saline and challenged i.v. with 1.0 x 10(6) conidia after 7, 15, or 21 days. No protection against challenge was found after 7 days. However, significant and reproducible protection was observed after 15 and 21 days. Mortality was reduced from 90% in control mice to 53% in preinfected mice 40 days after challenge (P = 0.0002). Increased survival was correlated with decreased content of chitin in lungs, liver, and kidneys 4 and 7 days after challenge (P < 0.05). Mice were again inoculated with 1.0 x 10(4) conidia or saline, and after 21 days, 1.0 x 10(8) or 2.0 x 10(8) splenocytes were transferred to naive syngeneic recipients; 2.0 x 10(8) immune splenocytes conferred significant protection (P = 0.0001) against i.v. challenge with 1.0 x 10(6) conidia, and mortality decreased from 83 to 48% 40 days after challenge. Transfer of immune serum offered no protection despite the presence of antibody against a hyphal homogenate of A. fumigatus, which was absent in the sera of control mice. Protection by immune splenocytes was maintained after selective depletion of T cells but was abolished after removal of plastic-adherent splenocytes. Adherent cells were characterized as macrophages by using morphological criteria, nonspecific esterase, and MAC-1 monoclonal antibody. Production of hydrogen peroxide by peritoneal and splenic macrophages from preinfected mice was the same as and lower than, respectively, that from uninfected controls. However, phagocytosis of conidia by peritoneal or splenic macrophages from mice preinfected i.v. or intratracheally was significantly increased after 2 and 3 h of coculture compared with that from uninfected animals, whereas in vitro killing of conidia by splenic macrophages was unaltered. Peritoneal or splenic macrophages from control or preinfected mice failed to kill hyphae in vitro. Killing of hyphae by polymorphonuclear leukocytes was not significantly different between mice preinfected i.v. and uninfected controls. Taken together, the results indicate that acquired immunity mediated by activated macrophages can be demonstrated in experimental murine aspergillosis.(ABSTRACT TRUNCATED AT 400 WORDS) Images PMID:8359900

de Repentigny, L; Petitbois, S; Boushira, M; Michaliszyn, E; Sénéchal, S; Gendron, N; Montplaisir, S

1993-01-01

37

Innate immune cells in transplantation  

PubMed Central

Purpose of review This review examines the recent literature on the role of innate cells in immunity to transplanted tissue. It specifically addresses the impact of monocytes/macrophages, neutrophils, NK cells, and platelets. Recent findings Current research indicates that innate immunity plays a dual role in response to transplanted tissue with the ability to either facilitate rejection or promote tolerance. Intriguingly, some of these cells are even capable of reacting to allogeneic cells, a feature usually only attributed to cells of the adaptive immune system. Summary This review highlights new therapeutic targets in the innate immune system that may be useful in the treatment of transplant recipients. It also emphasizes the need to use caution in exploring these new therapeutics. PMID:24316757

Spahn, Jessica H.; Li, Wenjun; Kreisel, Daniel

2014-01-01

38

Alkylamides from echinacea modulate induced immune responses in macrophages.  

PubMed

The ability of Echinacea and its components to alter the immune response was examined in vitro in a macrophage cell line under either basal or immunostimulated conditions. Potential immunostimulatory and inflammatory activity was determined using a nuclear transcription factor (NFkappaB) expression, tumour necrosis factor alpha (TNFalpha) and nitric oxide (NO) production as biomarkers. In the absence of alternate stimulation, the only significant effects seen were a decrease in NFkappaB expression by a 2-ene alkylamide ((2E)-N-isobutylundeca-2-ene-8,10-diynamide (1)) and a decrease in TNFalpha levels by cichoric acid and an Echinacea alkylamide fraction (EPL AA). When the cells were stimulated by lipopolysaccharide (LPS), inhibition of the increased NFkappaB expression levels was caused by cichoric acid, an Echinacea preparation (EPL), EPL AA and a 2,4-diene ((2E,4E,8Z,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamide (2)). Increases in TNFalpha levels were inhibited by cichoric acid, EPL and EPL AA but enhanced by 1 in the presence of LPS, while only EPL AA was able to inhibit the stimulated increases in NO. When using phorbol myristate acetate to stimulate the cells, NFkappaB and NO levels were unaffected by Echinacea or its components while only cichoric acid and 2 inhibited TNFalpha levels. Although cichoric acid was found to have an effect, it is probably not an important contributor to the Echinacea modulation of the immune response in vivo, as it is not bioavailable. Echinacea appears to attenuate the response of macrophages to an immune stimulus and its combination of phytochemicals exhibits different pharmacological properties to one or more of the isolated major individual components. PMID:17365014

Matthias, A; Banbury, L; Stevenson, L M; Bone, K M; Leach, D N; Lehmann, R P

2007-01-01

39

Role of macrophage receptor with collagenous structure in innate immune tolerance.  

PubMed

Macrophages play a key role in host defense against microbes, in part, through phagocytosis. Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor on the cell surface of macrophages that mediates opsonin-independent phagocytosis. The goal of our study is to investigate the role of MARCO in LPS or lipotechoic acid-induced macrophage tolerance. Although it has been established that expression of MARCO and phagocytosis is increased in tolerant macrophages, the transcriptional regulation and biological role of MARCO in tolerant macrophages have not been investigated. In this study, we confirm that tolerized mouse bone marrow-derived macrophages (BMDM) selectively increase expression of MARCO (both transcript and cell surface receptor) and increase phagocytosis. We found that H3K4me3 dynamic modification of a promoter site of MARCO was increased in tolerized BMDM. Blocking methylation by treatment with 5-aza-2'-deoxycytidine resulted in reduced H3K4me3 binding in the promoter of MARCO, decreased expression of MARCO, and impaired phagocytosis in tolerized BMDM. However, 5-aza-2'-deoxycytidine had no effect on the inflammatory component of innate immune tolerance. In aggregate, we found that histone methylation was critical to MARCO expression and phagocytosis in tolerized macrophages, but did not affect the inflammatory component of innate immune tolerance. PMID:23667110

Jing, Jian; Yang, Ivana V; Hui, Lucy; Patel, Jay A; Evans, Christopher M; Prikeris, Rytis; Kobzik, Lester; O'Connor, Brian P; Schwartz, David A

2013-06-15

40

Liposomal Cholesterol Delivery Activates the Macrophage Innate Immune Arm To Facilitate Intracellular Leishmania donovani Killing  

PubMed Central

Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-?) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm. PMID:24478076

Ghosh, June; Guha, Rajan; Das, Shantanabha

2014-01-01

41

Liposomal cholesterol delivery activates the macrophage innate immune arm to facilitate intracellular Leishmania donovani killing.  

PubMed

Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-?) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm. PMID:24478076

Ghosh, June; Guha, Rajan; Das, Shantanabha; Roy, Syamal

2014-02-01

42

Nuclear Receptors and Clearance of Apoptotic Cells: Stimulating the Macrophage’s Appetite  

PubMed Central

Clearance of apoptotic cells by macrophages occurs as a coordinated process to ensure tissue homeostasis. Macrophages play a dual role in this process; first, a rapid and efficient phagocytosis of the dying cells is needed to eliminate uncleared corpses that can promote inflammation. Second, after engulfment, macrophages exhibit an anti-inflammatory phenotype, to avoid unwanted immune reactions against cell components. Several nuclear receptors, including liver X receptor and proliferator-activated receptor, have been linked to these two important features of macrophages during apoptotic cell clearance. This review outlines the emerging implications of nuclear receptors in the response of macrophages to cell clearance. These include activation of genes implicated in metabolism, to process the additional cellular content provided by the engulfed cells, as well as inflammatory genes, to maintain apoptotic cell clearance as an “immunologically silent” process. Remarkably, genes encoding receptors for the so-called “eat-me” signals are also regulated by activated nuclear receptors after phagocytosis of apoptotic cells, thus enhancing the efficiency of macrophages to clear dead cells. PMID:24860573

A-Gonzalez, Noelia; Hidalgo, Andrés

2014-01-01

43

Tumour cell expression of B7 costimulatory molecules and interleukin-12 or granulocyte-macrophage colony-stimulating factor induces a local antitumour response and may generate systemic protective immunity.  

PubMed

Previously, we showed that expression of B7-1 in CMT93 murine colorectal tumour cells inhibited their growth in immunocompetent animals. However, this did not result in any significant increase in systemic protective immunity, relative to that elicited by the parental tumour. To potentiate the effects of B7-1 on systemic immunity. Interleukin-12 (IL-12) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was co-expressed with this molecule. These combinations of immunostimulatory molecules were effective in eliciting systemic immunity. We also show that expression of B7-2 led to a local antitumour response as well as significantly raised systemic immunity. In another tumour model. K1735 minutes melanoma, which is moderately immunogenic, tumours secreting GM-CSF alone were as effective as the parental tumours in generating protective immunity. Previously, we described the deleterious effect of B7-1 expression on protective immunity. Co-expression of GM-CSF did not counteract this consequence of B7-1 expression. Expression of IL-12 was extremely effective in causing rejection of inoculated tumour cells, but evoked only minimal protective systemic immunity. These results suggest that combing costimulatory molecules and cytokines may be a useful therapeutic approach in some, but not all, tumours. PMID:9578842

Chong, H; Todryk, S; Hutchinson, G; Hart, I R; Vile, R G

1998-02-01

44

Biofilm-derived Legionella pneumophila evades the innate immune response in macrophages.  

PubMed

Legionella pneumophila, the causative agent of Legionnaire's disease, replicates in human alveolar macrophages to establish infection. There is no human-to-human transmission and the main source of infection is L. pneumophila biofilms established in air conditioners, water fountains, and hospital equipments. The biofilm structure provides protection to the organism from disinfectants and antibacterial agents. L. pneumophila infection in humans is characterized by a subtle initial immune response, giving time for the organism to establish infection before the patient succumbs to pneumonia. Planktonic L. pneumophila elicits a strong immune response in murine, but not in human macrophages enabling control of the infection. Interactions between planktonic L. pneumophila and murine or human macrophages have been studied for years, yet the interface between biofilm-derived L. pneumophila and macrophages has not been explored. Here, we demonstrate that biofilm-derived L. pneumophila replicates significantly more in murine macrophages than planktonic bacteria. In contrast to planktonic L. pneumophila, biofilm-derived L. pneumophila lacks flagellin expression, do not activate caspase-1 or -7 and trigger less cell death. In addition, while planktonic L. pneumophila is promptly delivered to lysosomes for degradation, most biofilm-derived bacteria were enclosed in a vacuole that did not fuse with lysosomes in murine macrophages. This study advances our understanding of the innate immune response to biofilm-derived L. pneumophila and closely reproduces the natural mode of infection in human. PMID:23750338

Abu Khweek, Arwa; Fernández Dávila, Natalia S; Caution, Kyle; Akhter, Anwari; Abdulrahman, Basant A; Tazi, Mia; Hassan, Hoda; Novotny, Laura A; Bakaletz, Lauren O; Amer, Amal O

2013-01-01

45

Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting AntiTumor Immunity  

Microsoft Academic Search

To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells

Glenn Dranoff; Elizabeth Jaffee; Audrey Lazenby; Paul Golumbek; Hyam Levitsky; Katja Brose; Valerie Jackson; Hirofumi Hamada; Drew Pardoll; Richard C. Mulligan

1993-01-01

46

The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1  

PubMed Central

Little is known about the immune performance and interactions of CNS microglia/macrophages in glioma patients. We found that microglia/macrophages were the predominant immune cell infiltrating gliomas (~1% of total cells); others identified were myeloid dendritic cells (DCs), plasmacytoid DCs, and T cells. We isolated and analyzed the immune functions of CD11b/c+CD45+ glioma-infiltrating microglia/macrophages (GIMs) from postoperative tissue specimens of glioma patients. Although GIMs expressed substantial levels of Toll-like receptors (TLRs), they did not appear stimulated to produce pro-inflammatory cytokines (tumor necrosis factor ?, interleukin 1, or interleukin 6), and in vitro, lipopolysaccharides could bind TLR-4 but could not induce GIM-mediated T-cell proliferation. Despite surface major histocompatibility complex class II expression, they lacked expression of the costimulatory molecules CD86, CD80, and CD40 critical for T-cell activation. Ex vivo, we demonstrate a corresponding lack of effector/activated T cells, as glioma-infiltrating CD8+ T cells were phenotypically CD8+CD25?. By contrast, there was a prominent population of regulatory CD4 T cells (CD4+CD25+FOXP3+) infiltrating the tumor. We conclude that while GIMs may have a few intact innate immune functions, their capacity to be stimulated via TLRs, secrete cytokines, upregulate costimulatory molecules, and in turn activate antitumor effector T cells is not sufficient to initiate immune responses. Furthermore, the presence of regulatory T cells may also contribute to the lack of effective immune activation against malignant human gliomas. PMID:16775224

Hussain, S. Farzana; Yang, David; Suki, Dima; Aldape, Kenneth; Grimm, Elizabeth; Heimberger, Amy B.

2006-01-01

47

Dying to live: how the death modality of the infected macrophage affects immunity to tuberculosis.  

PubMed

Virulent Mycobacterium tuberculosis (Mtb) inhibits apoptosis and triggers necrosis of host macrophages to evade innate delay in the initiation of adaptive immunity. Necrosis is a mechanism used by bacteria to exit macrophage, evade the host defenses, and disseminate while apoptosis is associated with diminished pathogen viability. We have recently demonstrated that eicosanoids regulate cell death program of either human or murine macrophages infected with Mtb. We have defined prostaglandin E2 (PGE2) as a pro-apoptotic host lipid mediator which protects against necrosis. In contrast, lipoxin A4 (LXA4) is a pro-necrotic lipid mediator which suppresses PGE2 synthesis, resulting in mitochondrial damage and inhibition of plasma membrane repair mechanisms; this ultimately leads to the induction of necrosis. Thus, the balance between PGE2 and LXA4 determines whether Mtb-infected macrophages undergo apoptosis or necrosis and this balance determines the outcome of infection. PMID:23468106

Divangahi, Maziar; Behar, Samuel M; Remold, Heinz

2013-01-01

48

Bacterial cell envelopes (ghosts) and LPS but not bacterial S-layers induce synthesis of immune-mediators in mouse macrophages involving CD14  

Microsoft Academic Search

The synthesis of inflammatory mediators in human macrophages\\/monocytes seen after stimulation with lipopolysaccharide (LPS) involves the binding of CD14 to LPS complexed to lipopolysaccharide binding protein (LBP). The binding mechanisms of different LPS domains to LBP and CD14, as well as the interaction of the entire bacterial cell wall and its components with CD14 and LBP, are poorly understood. We,

A. G. Haslberger; H. J. Mader; M. Schmalnauer; G. Kohl; M. P. Szostak; P. Messner; U. B. Sleytr; G. Wanner; S. Fürst-Ladani; W. Lubitz

1997-01-01

49

Localized retinal neuropeptide regulation of macrophage and microglial cell functionality  

PubMed Central

The functionality of immune cells is manipulated within the ocular microenvironment to protect the sensitive and non-regenerating light-gathering tissue from the collateral damage of inflammation. This is mediated partly by the constitutive presence of immunomodulating neuropeptides. Treating primary resting macrophages with soluble factors produced by the posterior eye induced co-expression of Arginase1 and NOS2. The neuropeptides alpha-melanocyte stimulating hormone and Neuropeptide Y alternatively activated the macrophages to co-express Arginase1 and NOS2 like myeloid suppressor cells. Similar co-expressing cells were found within healthy, but not in wounded retinas. Therefore, the healthy retina regulates macrophage functionality to the benefit of ocular immune privilege. PMID:20965575

Kawanaka, Norikuni; Taylor, Andrew W.

2010-01-01

50

IgA and IgG immune complexes increase human macrophage C3 biosynthesis.  

PubMed Central

We have studied the effect of IgA- and IgG-containing immune complexes on the production of complement proteins C3, factor B and C2 by human monocyte-derived macrophages, using biosynthetic labelling, immunoprecipitation, sodium dodecyl sulphate-polyacrylamide gel (SDS-PAGE) and autoradiography. There was a consistent increase in C3 production and secretion with both IgA and IgG immune complexes. This increase appeared after a 24-hr incubation period of the macrophages in the presence of immune complexes. No change in the biosynthesis of factor B and C2 proteins was observed in these experiments. Concomitant with the enhanced C3 biosynthesis, the immune complexes caused an increase in macrophage tumour necrosis factor (TNF) production; 310 + 24 U/ml/5 x 10(5) cells and 430 + 51 U/ml/5 x 10(5) cells for IgA and IgG immune complexes, respectively, versus 12 + 8 U/ml/5 x 10(5) cells in the control cells. The presence of prednisolone (2 x 10(-5) M) or dexamethasone (1 x 10(-7) M) inhibited the immune complex-induced TNF production, but had no effect on C3-increased synthesis, suggesting that the effect of immune complexes was not mediated by endogenous TNF production. These findings may be relevant to the local inflammatory response in IgA immune complex-mediated diseases, including IgA nephropathy. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:7750996

Laufer, J; Boichis, H; Farzam, N; Passwell, J H

1995-01-01

51

PDT-treated apoptotic cells induce macrophage synthesis NO  

NASA Astrophysics Data System (ADS)

Nitric oxide (NO) is a biologically active molecule which has multi-functional in different species. As a second messenger and neurotransmitter, NO is not only an important regulatory factor between cells' information transmission, but also an important messenger in cell-mediated immunity and cytotoxicity. On the other side, NO is involving in some diseases' pathological process. In pathological conditions, the macrophages are activated to produce a large quantity of nitric oxide synthase (iNOS), which can use L-arginine to produce an excessive amount of NO, thereby killing bacteria, viruses, parasites, fungi, tumor cells, as well as in other series of the immune process. In this paper, photofrin-based photodynamic therapy (PDT) was used to treat EMT6 mammary tumors in vitro to induce apoptotic cells, and then co-incubation both apoptotic cells and macrophages, which could activate macrophage to induce a series of cytotoxic factors, especially NO. This, in turn, utilizes macrophages to activate a cytotoxic response towards neighboring tumor cells. These results provided a new idea for us to further study the immunological mechanism involved in damaging effects of PDT, also revealed the important function of the immune effect of apoptotic cells in PDT.

Song, S.; Xing, D.; Zhou, F. F.; Chen, W. R.

2009-11-01

52

Immune Evasion, Stress Resistance, and Efficient Nutrient Acquisition Are Crucial for Intracellular Survival of Candida glabrata within Macrophages  

PubMed Central

Candida glabrata is both a human fungal commensal and an opportunistic pathogen which can withstand activities of the immune system. For example, C. glabrata can survive phagocytosis and replicates within macrophages. However, the mechanisms underlying intracellular survival remain unclear. In this work, we used a functional genomic approach to identify C. glabrata determinants necessary for survival within human monocyte-derived macrophages by screening a set of 433 deletion mutants. We identified 23 genes which are required to resist killing by macrophages. Based on homologies to Saccharomyces cerevisiae orthologs, these genes are putatively involved in cell wall biosynthesis, calcium homeostasis, nutritional and stress response, protein glycosylation, or iron homeostasis. Mutants were further characterized using a series of in vitro assays to elucidate the genes' functions in survival. We investigated different parameters of C. glabrata-phagocyte interactions: uptake by macrophages, replication within macrophages, phagosomal pH, and recognition of mutant cells by macrophages as indicated by production of reactive oxygen species and tumor necrosis factor alpha (TNF-?). We further studied the cell surface integrity of mutant cells, their ability to grow under nutrient-limited conditions, and their susceptibility to stress conditions mirroring the harsh environment inside a phagosome. Additionally, resistance to killing by neutrophils was analyzed. Our data support the view that immune evasion is a key aspect of C. glabrata virulence and that increased immune recognition causes increased antifungal activities by macrophages. Furthermore, stress resistance and efficient nutrient acquisition, in particular, iron uptake, are crucial for intraphagosomal survival of C. glabrata. PMID:24363366

Seider, Katja; Gerwien, Franziska; Kasper, Lydia; Allert, Stefanie; Brunke, Sascha; Jablonowski, Nadja; Schwarzmüller, Tobias; Barz, Dagmar; Rupp, Steffen; Kuchler, Karl

2014-01-01

53

DNA-Protein Immunization Using Leishmania Peroxidoxin-1 Induces a Strong CD4+ T Cell Response and Partially Protects Mice from Cutaneous Leishmaniasis: Role of Fusion Murine Granulocyte-Macrophage Colony-Stimulating Factor DNA Adjuvant  

PubMed Central

Background To date, no universally effective and safe vaccine has been developed for general human use. Leishmania donovani Peroxidoxin-1 (LdPxn-1) is a member of the antioxidant family of proteins and is predominantly expressed in the amastigote stage of the parasite. The aim of this study was to evaluate the immunogenicity and protective efficacy of LdPxn-1 in BALB/c mice in heterologous DNA-Protein immunization regimen in the presence of fusion murine granulocyte-macrophage colony-stimulating factor (mGMCSF) DNA adjuvant. Methodology and Principal Findings A fusion DNA of LdPxn1 and mGMCSF was cloned into a modified pcDNA vector. To confirm the expression in mammalian system, Chinese hamster ovary cells were transfected with the plasmid vector containing LdPxn1 gene. BALB/c mice were immunized twice with pcDNA-mGMCSF-LdPxn-1 or pcDNA-LdPxn1 DNA and boosted once with recombinant LdPxn-1 protein. Three weeks after the last immunization, mice were infected with Leishmania major promastigotes. The result showed that immunization with pcDNA-mGMCSF-LdPxn1 elicited a mixed Th-1/Th-2 immune response with significantly higher production of IFN-? than controls. Intracellular cytokine staining of antigen-stimulated spleen cells showed that immunization with this antigen elicited significantly higher proportion of CD4+ T cells that express IFN-?, TNF-?, or IL-2. The antigen also induced significantly higher proportion of multipotent CD4+ cells that simultaneously express the three Th-1 cytokines. Moreover, a significant reduction in the footpad swelling was seen in mice immunized with pcDNA-mGMCSF-LdPxn1 antigen. Expression study in CHO cells demonstrated that pcDNA-mGMCSF-LdPxn-1 was expressed in mammalian system. Conclusion The result demonstrates that immunization of BALB/c mice with a plasmid expressing LdPxn1 in the presence of mGMCSF adjuvant elicits a strong specific immune response with high level induction of multipotent CD4+ cells that mediate protection of the mice from Leishmania major infection. To our knowledge, this is the first study showing the vaccine potential of Leishmania peroxidoxin -1. PMID:25500571

Bayih, Abebe Genetu; Daifalla, Nada S.; Gedamu, Lashitew

2014-01-01

54

Absence of Monocyte Chemoattractant Protein 1 in Mice Leads to Decreased Local Macrophage Recruitment and Antigen-Specific T Helper Cell Type 1 Immune Response in Experimental Autoimmune Encephalomyelitis  

PubMed Central

Monocyte chemoattractant protein (MCP)-1 plays a critical role in innate immunity by directing the migration of monocytes into inflammatory sites. Recent data indicated a function for this chemokine in adaptive immunity as a regulator of T cell commitment to T helper cell type 2 (Th2) effector function. Studies in a Th1-dependent animal model, experimental autoimmune encephalomyelitis (EAE), showed that MCP-1 was highly expressed in the central nervous system (CNS) of affected rodents, and MCP-1 antibodies could block relapses of the disease. Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients. We analyzed EAE in mice deficient for MCP-1 to define the relevant ligand for CCR2, which responds to murine MCP-1, MCP-2, MCP-3, and MCP-5. We found that C57BL/6 MCP-1–null mice were markedly resistant to EAE after active immunization, with drastically impaired recruitment of macrophages to the CNS, yet able to generate effector T cells that transferred severe disease to naive wild-type recipients. By contrast, adoptive transfer of primed T cells from wild-type mice into naive MCP-1–null recipients did not mediate clinical EAE. On the SJL background, disruption of the MCP-1 gene produced a milder EAE phenotype with diminished relapses that mimicked previous findings using anti–MCP-1 antibodies. There was no compensatory upregulation of MCP-2, MCP-3, or MCP-5 in MCP-1–null mice with EAE. These results indicated that MCP-1 is the major CCR2 ligand in mice with EAE, and provided an opportunity to define the role of MCP-1 in EAE. Compared with wild-type littermates, MCP-1?/? mice exhibited reduced expression of interferon ? in draining lymph node and CNS and increased antigen-specific immunoglobulin G1 antibody production. Taken together, these data demonstrate that MCP-1 is crucial for Th1 immune responses in EAE induction and that macrophage recruitment to the inflamed CNS target organ is required for primed T cells to execute a Th1 effector program in EAE. PMID:11257138

Huang, DeRen; Wang, Jintang; Kivisakk, Pia; Rollins, Barrett J.; Ransohoff, Richard M.

2001-01-01

55

Immune cells in term and preterm labor  

PubMed Central

Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm. PMID:24954221

Gomez-Lopez, Nardhy; StLouis, Derek; Lehr, Marcus A; Sanchez-Rodriguez, Elly N; Arenas-Hernandez, Marcia

2014-01-01

56

Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori.  

PubMed

Helicobacter pylori incites a futile inflammatory response, which is the key feature of its immunopathogenesis. This leads to the ability of this bacterial pathogen to survive in the stomach and cause peptic ulcers and gastric cancer. Myeloid cells recruited to the gastric mucosa during H. pylori infection have been directly implicated in the modulation of host defense against the bacterium and gastric inflammation. Heme oxygenase-1 (HO-1) is an inducible enzyme that exhibits anti-inflammatory functions. Our aim was to analyze the induction and role of HO-1 in macrophages during H. pylori infection. We now show that phosphorylation of the H. pylori virulence factor cytotoxin-associated gene A (CagA) in macrophages results in expression of hmox-1, the gene encoding HO-1, through p38/NF (erythroid-derived 2)-like 2 signaling. Blocking phagocytosis prevented CagA phosphorylation and HO-1 induction. The expression of HO-1 was also increased in gastric mononuclear cells of human patients and macrophages of mice infected with cagA(+) H. pylori strains. Genetic ablation of hmox-1 in H. pylori-infected mice increased histologic gastritis, which was associated with enhanced M1/Th1/Th17 responses, decreased regulatory macrophage (Mreg) response, and reduced H. pylori colonization. Gastric macrophages of H. pylori-infected mice and macrophages infected in vitro with this bacterium showed an M1/Mreg mixed polarization type; deletion of hmox-1 or inhibition of HO-1 in macrophages caused an increased M1 and a decrease of Mreg phenotype. These data highlight a mechanism by which H. pylori impairs the immune response and favors its own survival via activation of macrophage HO-1. PMID:25108023

Gobert, Alain P; Verriere, Thomas; Asim, Mohammad; Barry, Daniel P; Piazuelo, M Blanca; de Sablet, Thibaut; Delgado, Alberto G; Bravo, Luis E; Correa, Pelayo; Peek, Richard M; Chaturvedi, Rupesh; Wilson, Keith T

2014-09-15

57

Tumoral Immune Suppression by Macrophages Expressing Fibroblast Activation Protein-Alpha and Heme Oxygenase-1  

PubMed Central

The depletion of tumor stromal cells that are marked by their expression of the membrane protein fibroblast activation protein-? (FAP) overcomes immune suppression and allows an anti-cancer cell immune response to control tumor growth. In subcutaneous tumors established with immunogenic Lewis lung carcinoma cells expressing ovalbumin (LL2/OVA), the FAP+ population comprises CD45+ and CD45? cells. In the present study, we further characterize the tumoral FAP+/CD45+ population as a minor sub-population of F4/80hi/CCR2+/CD206+ M2 macrophages. Using bone marrow chimeric mice in which the primate diphtheria toxin receptor (DTR) is restricted either to the FAP+/CD45+ or to the FAP+/CD45? subset, we demonstrate by conditionally depleting each subset that both independently contribute to the immune suppressive tumor microenvironment. A basis for the function of the FAP+/CD45+ subset is shown to be the immune inhibitory enzyme, heme oxygenase-1 (HO-1). The FAP+/CD45+ cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Since this observation of immune suppression by HO-1 expressed by the FAP+/CD45+ stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy. PMID:24778275

Arnold, James N.; Magiera, Lukasz; Kraman, Matthew; Fearon, Douglas T.

2013-01-01

58

Isolation of functional cardiac immune cells.  

PubMed

Cardiac immune cells are gaining interest for the roles they play in the pathological remodeling in many cardiac diseases. These immune cells, which include mast cells, T-cells and macrophages; store and release a variety of biologically active mediators including cytokines and proteases such as tryptase. These mediators have been shown to be key players in extracellular matrix metabolism by activating matrix metalloproteinases or causing collagen accumulation by modulating the cardiac fibroblasts' function. However, available techniques for isolating cardiac immune cells have been problematic because they use bacterial collagenase to digest the myocardial tissue. This technique causes activation of the immune cells and thus a loss of function. For example, cardiac mast cells become significantly less responsive to compounds that cause degranulation. Therefore, we developed a technique that allows for the isolation of functional cardiac immune cells which would lead to a better understanding of the role of these cells in cardiac disease. This method requires a familiarity with the anatomical location of the rat's xiphoid process, axilla and falciform ligament, and pericardium of the heart. These landmarks are important to increase success of the procedure and to ensure a higher yield of cardiac immune cells. These isolated cardiac immune cells can then be used for characterization of functionality, phenotype, maturity, and co-culture experiments with other cardiac cells to gain a better understanding of their interactions. PMID:22158428

McLarty, Jennifer L; Meléndez, Giselle C; Spencer, William J; Levick, Scott P; Brower, Gregory L; Janicki, Joseph S

2011-01-01

59

Chemoattractant Signaling between Tumor Cells and Macrophages Regulates Cancer Cell Migration, Metastasis and Neovascularization  

PubMed Central

Tumor-associated macrophages are known to influence cancer progression by modulation of immune function, angiogenesis, and cell metastasis, however, little is known about the chemokine signaling networks that regulate this process. Utilizing CT26 colon cancer cells and RAW 264.7 macrophages as a model cellular system, we demonstrate that treatment of CT26 cells with RAW 264.7 conditioned medium induces cell migration, invasion and metastasis. Inflammatory gene microarray analysis indicated CT26-stimulated RAW 264.7 macrophages upregulate SDF-1? and VEGF, and that these cytokines contribute to CT26 migration in vitro. RAW 264.7 macrophages also showed a robust chemotactic response towards CT26-derived chemokines. In particular, microarray analysis and functional testing revealed CSF-1 as the major chemoattractant for RAW 264.7 macrophages. Interestingly, in the chick CAM model of cancer progression, RAW 264.7 macrophages localized specifically to the tumor periphery where they were found to increase CT26 tumor growth, microvascular density, vascular disruption, and lung metastasis, suggesting these cells home to actively invading areas of the tumor, but not the hypoxic core of the tumor mass. In support of these findings, hypoxic conditions down regulated CSF-1 production in several tumor cell lines and decreased RAW 264.7 macrophage migration in vitro. Together our findings suggest a model where normoxic tumor cells release CSF-1 to recruit macrophages to the tumor periphery where they secrete motility and angiogenic factors that facilitate tumor cell invasion and metastasis. PMID:19696929

Green, Chad E.; Liu, Tiffany; Montel, Valerie; Hsiao, Gene; Lester, Robin D.; Subramaniam, Shankar; Gonias, Steven L.; Klemke, Richard L.

2009-01-01

60

Diverse influences of androgen-disrupting chemicals on immune responses mounted by macrophages.  

PubMed

Androgen-disrupting chemicals (ADCs) can alter male sexual development. Although the effects of ADCs on hormone disruption have been studied, their influence on the immune response is not fully understood. To investigate the effects of ADCs on innate immunity, we tested eight candidate ADCs for their influence on macrophages by measuring nitric oxide (NO) production and cell viability. Our results showed that treatment with a mixture of lipopolysaccharide and hexachlorobenzene increased NO production in RAW 264.7 cells, a murine macrophage cell line. In contrast, compared to exposure to a negative control, exposure to di-2-ethylhexyl adipate (DEHA), benzylbutyl phthalate (BBP), testosterone (TTT), or permethrin decreased NO production. DEHA, BBP, and TTT inhibited NO production in an inducible nitric oxide synthase-dependent manner. Treatment with bisphenol A (BPA), nonylphenol (NNP), or tributyltin chloride (TBTC) reduced NO production and induced cell death. While BPA induced RAW 264.7 cell death through apoptosis, NNP and TBTC caused cell death through necrosis. These results offer insights into the influences of ADCs on the innate immune system. PMID:24287822

Kim, Kyong Hoon; Yeon, Seung-min; Kim, Hyun Gyung; Choi, Hyun Suk; Kang, Hyojeung; Park, Hee-Deung; Park, Tae Won; Pack, Seung Pil; Lee, Eun Hee; Byun, Youngjoo; Choi, Sang-Eun; Lee, Kenneth Sung; Ha, Un-Hwan; Jung, Yong Woo

2014-06-01

61

Role of macrophages in the immune response to hepatocytes  

Microsoft Academic Search

The purpose of this study was to determine the role of host macrophages in the development of allospecific cytolytic T cells (allo-CTLs) in response to purified allogeneic MHC Class I+, Class II- hepatocytes in vivo in hepatocyte sponge matrix allografts (HC-SMA). Depletion of antigen-presenting cells (APCs) from responder splenocytes in mixed lymphocyte hepatocyte culture (MLHC) inhibits the development of allo-CTLs

G. L. Bumgardner; S. Chen; S. P. Almond; N. L. Ascher; W. D. Payne; A. J. Matas

1990-01-01

62

T Cell–Macrophage Interactions and Granuloma Formation in Vasculitis  

PubMed Central

Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a typical event in inflammatory blood vessel diseases, and is noted in the name of several of the vasculitides. It is not known whether specific properties of the microenvironment in the blood vessel wall or the immediate surroundings of blood vessels contribute to granuloma formation and, in some cases, generation of multinucleated giant cells. Granulomas provide a specialized niche to optimize macrophage–T cell interactions, strongly activating both cell types. This is mirrored by the intensity of the systemic inflammation encountered in patients with vasculitis, often presenting with malaise, weight loss, fever, and strongly upregulated acute phase responses. As a sophisticated and highly organized structure, granulomas can serve as an ideal site to induce differentiation and maturation of T cells. The granulomas possibly seed aberrant Th1 and Th17 cells into the circulation, which are known to be the main pathogenic cells in vasculitis. Through the induction of memory T cells, aberrant innate immune responses can imprint the host immune system for decades to come and promote chronicity of the disease process. Improved understanding of T cell–macrophage interactions will redefine pathogenic models in the vasculitides and provide new avenues for immunomodulatory therapy. PMID:25309534

Hilhorst, Marc; Shirai, Tsuyoshi; Berry, Gerald; Goronzy, Jörg J.; Weyand, Cornelia M.

2014-01-01

63

LPS-induced down-regulation of signal regulatory protein {alpha} contributes to innate immune activation in macrophages.  

PubMed

Activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-kappaB) cascades after Toll-like receptor (TLR) stimulation contributes to innate immune responses. Signal regulatory protein (SIRP) alpha, a member of the SIRP family that is abundantly expressed in macrophages, has been implicated in regulating MAPK and NF-kappaB signaling pathways. In addition, SIRPalpha can negatively regulate the phagocytosis of host cells by macrophages, indicating an inhibitory role of SIRPalpha in innate immunity. We provide evidences that SIRPalpha is an essential endogenous regulator of the innate immune activation upon lipopolysaccharide (LPS) exposure. SIRPalpha expression was promptly reduced in macrophages after LPS stimulation. The decrease in SIRPalpha expression levels was required for initiation of LPS-induced innate immune responses because overexpression of SIRPalpha reduced macrophage responses to LPS. Knockdown of SIRPalpha caused prolonged activation of MAPKs and NF-kappaB pathways and augmented production of proinflammatory cytokines and type I interferon (IFN). Mice transferred with SIRPalpha-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRPalpha may accomplish this mainly through its association and sequestration of the LPS signal transducer SHP-2. Thus, SIRPalpha functions as a biologically important modulator of TLR signaling and innate immunity. PMID:17954568

Kong, Xiao-Ni; Yan, He-Xin; Chen, Lei; Dong, Li-Wei; Yang, Wen; Liu, Qiong; Yu, Le-Xing; Huang, Dan-Dan; Liu, Shu-Qin; Liu, Hui; Wu, Meng-Chao; Wang, Hong-Yang

2007-10-29

64

Hyphal Growth of Phagocytosed Fusarium oxysporum Causes Cell Lysis and Death of Murine Macrophages  

PubMed Central

Fusarium oxysporum is an important plant pathogen and an opportunistic pathogen of humans. Here we investigated phagocytosis of F. oxysporum by J774.1 murine cell line macrophages using live cell video microscopy. Macrophages avidly migrated towards F. oxysporum germlings and were rapidly engulfed after cell-cell contact was established. F. oxysporum germlings continued hyphal growth after engulfment by macrophages, leading to associated macrophage lysis and escape. Macrophage killing depended on the multiplicity of infection. After engulfment, F. oxysporum inhibited macrophages from completing mitosis, resulting in large daughter cells fused together by means of a F. oxysporum hypha. These results shed new light on the initial stages of Fusarium infection and the innate immune response of the mammalian host. PMID:25025395

Schäfer, Katja; Bain, Judith M.

2014-01-01

65

Kinase AKT controls innate immune cell development and function  

PubMed Central

The critical roles of kinase AKT in tumour cell proliferation, apoptosis and protein synthesis have been widely recognized. But AKT also plays an important role in immune modulation. Recent studies have confirmed that kinase AKT can regulate the development and functions of innate immune cells (neutrophil, macrophage and dendritic cell). Studies have shown that different isoforms of kinase AKT have different effects in regulating immunity-related diseases, mainly through the mammalian target of rapamycin-dependent or -independent pathways. The purpose of this review is to illustrate the immune modulating effects of kinase AKT on innate immune cell development, survival and function. PMID:23692658

Zhang, Yan; Wang, Xiao; Yang, Hui; Liu, Huanrong; Lu, Yun; Han, Limei; Liu, Guangwei

2013-01-01

66

Cell-cell contacts with epithelial cells modulate the phenotype of human macrophages.  

PubMed

Interactions of macrophages with epithelium represent one of the pathways involved in regulating local immune mechanisms. We studied the effect of cell-cell contact with an epithelial monolayer on the phenotype of macrophages. Human monocytes and THP-1 macrophages were co-cultured with monolayers of human bronchial epithelial cells (HBECs), the alveolar type II-like cell line A549, renal adenocarcinoma epithelial cells (RA), and the lung fibroblast strain HFL-1. The expression of CD11b, CD14, CD54, and HLA-DR was measured by immunocytochemistry and flow cytometry and showed epithelial cell induction of CD54 and HLA-DR in monocytes and of all antigens in THP-1 cells. Co-culture with fibroblasts did not change the phenotype of macrophages. Separation by a filter insert inhibited most of the effects. Culture supernatants did not induce prominent phenotypic changes. Cell-cell contacts with epithelium appear to be of importance in regulating the phenotype of macrophages. PMID:11580100

Striz, I; Slavcev, A; Kalanin, J; Jaresová, M; Rennard, S I

2001-08-01

67

Macrophages: The "Defense" Cells That Help Throughout the Body  

NSDL National Science Digital Library

Press Release on research from David Mosser, Professor of Cell Biology and Molecular Genetics at the University of MarylandÂ?s College of Chemical and Life Sciences, about the three primary duties of macrophages. His work was presented at the 2010 American Physiological Society conference, Inflammation, Immunity, and Cardiovascular Disease, in Westminster Colorado, August 25-28. The full conference program can be found at http://the-aps.org/meetings/aps/inflammation/.

APS Communications Office (American Physiological Society Communications Office)

2010-08-26

68

Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization.  

PubMed

Freund's adjuvant produced severe inflammation that augments development of antibodies. Thus, mixed administration of antigens with adjuvant was not required as long as inflammation was induced in the hosts. Since macrophage activation for phagocytosis and antigen processing is the first step of antibody development, inflammation-primed macrophage activation plays a major role in immune development. Therefore, macrophage activating factor should act as an adjuvant for immunization. The inflammation-primed macrophage activation process is the major macrophage activating cascade that requires participation of serum vitamin D3-binding protein (DBP; human DBP is known as Gc protein) and glycosidases of B and T lymphocytes. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase efficiently generated the most potent macrophage activating factor (designated GcMAF) we have ever encountered. Administration of GcMAF (20 or 100 pg/mouse) resulted in stimulation of the progenitor cells for extensive mitogenesis and activation of macrophages. Administration of GcMAF (100 pg/mouse) along with immunization of mice with sheep red blood cells (SRBC) produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days. Thus, GcMAF has a potent adjuvant activity for immunization. Although malignant tumours are poorly immunogenic, 4 days after GcMAF-primed immunization of mice with heat-killed Ehrlich ascites tumour cells, the ascites tumour was no longer transplantable in these mice. PMID:9682967

Yamamoto, N; Naraparaju, V R

1998-06-01

69

20S-dihydroprotopanaxadiol, a ginsenoside derivative, boosts innate immune responses of monocytes and macrophages  

PubMed Central

20S-dihydroprotopanaxadiol (2H-PPD) is a derivative of protopanaxadiol, a glycone of ginsenosides prepared from Panax ginseng. Although ginsenosides and acidic polysaccharides are known to be major active ingredients in ginseng, the immunopharmacological activities of their metabolites and derivatives have not been fully explored. In this study, we aimed to elucidate the regulatory action of 2H-PPD on the function of monocytes and macrophages in innate immune responses. 2H-PPD was able to boost the phagocytic uptake of fluorescein isothiocyanate-dextran in macrophages and enhance the generation of radicals (reactive oxygen species) in sodium nitroprusside-treated RAW264.7 cells. The surface levels of the costimulatory molecules such as CD80 and CD86 were also increased during 2H-PPD treatment. In addition, this compound boosted U937 cellcell aggregation induced by CD29 and CD43 antibodies, but not by cell-extracellular matrix (fibronectin) adhesion. Similarly, the surface levels of CD29 and CD43 were increased by 2H-PPD exposure. Therefore, our results strongly suggest that 2H-PPD has the pharmacological capability to upregulate the functional role of macrophages/monocytes in innate immunity. PMID:24198654

Kim, Mi-Yeon; Cho, Jae Youl

2013-01-01

70

Killing of Edwardsiella ictaluri by macrophages from channel catfish immune and susceptible to enteric septicemia of catfish.  

PubMed

The role of peritoneal macrophages in immunity to enteric septicemia of catfish (ESC) after infection with live Edwardsiella ictaluri was investigated. Channel catfish macrophage-mediated bacteriocidal activity was dependent on the macrophage:bacteria ratio. Ratios of 1:1 to 1:12 exhibited significant differences (P < or = 0.05) in killing between macrophages from immune fish when compared to killing by macrophages from susceptible fish at 2.5 h. At 5 h, macrophages from immune fish were capable of effective killing (83.3%) at a 1:24 effector:target ratio, whereas macrophages from susceptible fish killed significantly (P < or = 0.05) less (56.9%). Macrophage bacteriocidal activity was significantly greater (P < or = 0.05) in macrophages from individual immune fish (93.4%) compared to macrophages from individual susceptible fish (85.4%). The kinetics of macrophage killing showed a linear increase in bacteriocidal activity from 1 to 3 h. Opsonization with immune serum enabled macrophages from immune fish to kill bacteria more effectively (93.8 vs. 75.9%) at 2.5 h. Opsonization of E. ictaluri with immune serum significantly suppressed the killing ability of macrophages from susceptible fish (46.2%) at 2.5 h. The results suggest that macrophages from fish immune to ESC had a greater capacity to kill E. ictaluri than macrophages from susceptible fish especially when E. ictaluri were opsonized with anti-E. ictaluri antibody. PMID:9336886

Shoemaker, C A; Klesius, P H; Plumb, J A

1997-09-01

71

EFFECTS OF ENVIRONMENTAL CONTAMINANTS ON CELL MEDIATED IMMUNITY  

EPA Science Inventory

The effect of lead and cadmium on cell-mediated immunity was studied in peritoneal macrophages, B-, and T-lymphocytes of mice. Lead and cadmium were administered in drinking water for 10 weeks in short-term experiments and up to 18 months to deal with immune responses in aged mic...

72

Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium  

PubMed Central

Dendritic cells (DCs), monocytes, and macrophages are closely related phagocytes that share many phenotypic features and, in some cases, a common developmental origin. Although the requirement for DCs in initiating adaptive immune responses is well appreciated, the role of monocytes and macrophages remains largely undefined, in part because of the lack of genetic tools enabling their specific depletion. Here, we describe a two-gene approach that requires overlapping expression of LysM and Csf1r to define and deplete monocytes and macrophages. The role of monocytes and macrophages in immunity to pathogens was tested by their selective depletion during infection with Citrobacter rodentium. Although neither cell type was required to initiate immunity, monocytes and macrophages contributed to the adaptive immune response by secreting IL-12, which induced Th1 polarization and IFN-? secretion. Thus, whereas DCs are indispensable for priming naive CD4+ T cells, monocytes and macrophages participate in intestinal immunity by producing mediators that direct T cell polarization. PMID:24043764

Schreiber, Heidi A.; Loschko, Jakob; Karssemeijer, Roos A.; Escolano, Amelia; Meredith, Matthew M.; Mucida, Daniel; Guermonprez, Pierre

2013-01-01

73

Cell Elasticity Determines Macrophage Function  

E-print Network

Macrophages serve to maintain organ homeostasis in response to challenges from injury, inflammation, malignancy, particulate exposure, or infection. Until now, receptor ligation has been understood as being the central ...

Patel, Naimish R.

74

Macrophages Contribute to the Cyclic Activation of Adult Hair Follicle Stem Cells  

PubMed Central

Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer. PMID:25536657

Castellana, Donatello; Paus, Ralf; Perez-Moreno, Mirna

2014-01-01

75

?? T Cell and Other Immune Cells Crosstalk in Cellular Immunity  

PubMed Central

?? T cells have been recognized as effectors with immunomodulatory functions in cellular immunity. These abilities enable them to interact with other immune cells, thus having the potential for treatment of various immune-mediated diseases with adoptive cell therapy. So far, the interactions between ?? T cell and other immune cells have not been well defined. Here we will discuss the interactivities among them and the perspective on ?? T cells for their use in immunotherapy could be imagined. The understanding of the crosstalk among the immune cells in immunopathology might be beneficial for the clinical application of ?? T cell. PMID:24741636

He, Ying; Wu, Kangni; Hu, Yongxian; Sheng, Lixia; Tie, Ruxiu; Wang, Binsheng; Huang, He

2014-01-01

76

Killing of Edwardsiella ictaluri by macrophages from channel catfish immune and susceptible to enteric septicemia of catfish  

Microsoft Academic Search

The role of peritoneal macrophages in immunity to enteric septicemia of catfish (ESC) after infection with live Edwardsiella ictaluri was investigated. Channel catfish macrophage-mediated bacteriocidal activity was dependent on the macrophage:bacteria ratio. Ratios of 1:1 to 1:12 exhibited significant differences (P ? 0.05) in killing between macrophages from immune fish when compared to killing by macrophages from susceptible fish at

Craig A. Shoemaker; Phillip H. Klesius; John A. Plumb

1997-01-01

77

Thematic review series: the immune system and atherogenesis. Recent insights into the biology of macrophage scavenger receptors.  

PubMed

Scavenger receptors were originally defined by their ability to bind and internalize modified lipoproteins. Macrophages express at least six structurally different cell surface receptors for modified forms of LDL that contribute to foam cell formation in atherosclerosis. In addition to their role in the pathology of atherosclerosis, macrophage scavenger receptors, especially SR-A, play critical roles in innate immunity, apoptotic cell clearance, and tissue homeostasis. In this review, we highlight recent advances in understanding the biology of macrophage scavenger receptors as pattern recognition receptors for both infectious nonself (pathogens) and modified self (apoptotic cells and modified LDL). We critically evaluate the potential of scavenger receptors and their ligands as targets for therapeutic intervention in human disease. PMID:15548472

Greaves, David R; Gordon, Siamon

2005-01-01

78

Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus  

PubMed Central

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have compared the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative [VL?], n = 37) to that of primary macrophages from HCV genotype 1 chronically infected (VL+) subjects (n = 32) and found that macrophages from VL? subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulated ex vivo through the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL? subjects. Furthermore, macrophages from VL? subjects showed higher production of beta interferon (IFN-?) and related IFN response genes by quantitative PCR (Q-PCR) and increased phosphorylation of STAT-1 by immunoblotting. Analysis of polymorphisms in TLR3 revealed a significant association of intronic TLR3 polymorphism (rs13126816) with the clearance of HCV and the expression of TLR3. Of note, peripheral blood mononuclear cells (PBMCs) from the same donors showed opposite changes in gene expression, suggesting ongoing inflammatory responses in PBMCs from VL+ HCV patients. Our results suggest that an elevated innate immune response enhances HCV clearance mechanisms and may offer a potential therapeutic approach to increase viral clearance. PMID:23220997

Qian, Feng; Bolen, Christopher R.; Jing, Chunxia; Wang, Xiaomei; Zheng, Wei; Zhao, Hongyu; Fikrig, Erol; Bruce, R. Douglas; Kleinstein, Steven H.

2013-01-01

79

Trophoblast debris modulates the expression of immune proteins in macrophages: a key to maternal tolerance of the fetal allograft?  

PubMed

Interactions between maternal immune cells and the placenta are of substantial interest since diseases of pregnancy, such as recurrent miscarriage, villitis of unknown etiology and preeclampsia may arise due to inadequate adaptation of the maternal immune system. During normal pregnancy trophoblast debris is shed from the placenta into the maternal blood in large quantities. This trophoblast debris is then rapidly cleared from the maternal circulation. In this study, we exposed trophoblast debris generated from an in vitro placental explant model to peripheral blood-derived macrophages and quantified a variety of molecules that are important in immune responses by ELISA or flow cytometry. Phagocytosis of trophoblast debris resulted in reduced cell-surface expression of MHC-II molecules, the costimulatory molecules (CD80, CD86, CD40 and B7H3), monocyte chemoattractant protein-1 (MCP-1), inter-cellular adhesion molecule 1 (ICAM-1) and IL-8 receptors in macrophages while the expression of programmed death-1 ligand 1 (PD-L1) was upregulated. In addition, phagocytosis of trophoblast debris induced the secretion of the anti-inflammatory cytokines IL-10, IL6 and IL1Ra and decreased the secretion of pro-inflammatory cytokines IL-1?, IL12p70 and IL-8 by macrophages. Phagocytosis of trophoblast debris also increased macrophage expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). We have shown that phagocytosis of trophoblast debris from normal placentae alters the phenotype of macrophages such that they are likely to deviate maternal immune responses towards tolerance and away from inflammation. This may be one of the mechanisms that allow the human fetal allograft to survive in direct contact with the maternal immune system. PMID:22542910

Abumaree, M H; Chamley, L W; Badri, M; El-Muzaini, M F

2012-06-01

80

Biodegradation of carbon nanohorns in macrophage cells.  

PubMed

With the rapid developments in the medical applications of carbon nanomaterials such as carbon nanohorns (CNHs), carbon nanotubes, and graphene based nanomaterials, understanding the long-term fate, health impact, excretion, and degradation of these materials has become crucial. Herein, the in vitro biodegradation of CNHs was determined using a non-cellular enzymatic oxidation method and two types of macrophage cell lines. Approximately 60% of the CNHs was degraded within 24 h in a phosphate buffer solution containing myeloperoxidase. Furthermore, approximately 30% of the CNHs was degraded by both RAW 264.7 and THP-1 macrophage cells within 9 days. Inflammation markers such as pro-inflammatory cytokines interleukin 6 and tumor necrosis factor ? were not induced by exposure to CNHs. However, reactive oxygen species were generated by the macrophage cells after uptake of CNHs, suggesting that these species were actively involved in the degradation of the nanomaterials rather than in an inflammatory pathway induction. PMID:25597450

Zhang, Minfang; Yang, Mei; Bussy, Cyrill; Iijima, Sumio; Kostarelos, Kostas; Yudasaka, Masako

2015-02-01

81

Immune Regulation by Rapamycin: Moving Beyond T Cells  

NSDL National Science Digital Library

The mammalian target of rapamycin (mTOR) is a multifunctional kinase that promotes cell growth and division in response to growth factor and nutrient signals. Rapamycin exerts its potent immunosuppressive effects in part through direct effects on antigen-specific lymphocytes; however, rapamycin also modulates adaptive immunity through its effects on innate immune cells, including dendritic cells and macrophages. Studies have established rapamycin-sensitive functions of mTOR, downstream of Toll-like receptors, in shaping the cytokine response of myeloid cells and driving the production of interferon by plasmacytoid dendritic cells. These findings point to new strategies for boosting or suppressing specific immune responses.

Matthew R. Janes (Irvine;University of California REV); David A. Fruman (Irvine;University of California REV)

2009-04-21

82

HF-LPLI-treated tumor cells induce NO production in macrophage  

NASA Astrophysics Data System (ADS)

High fluence low-power laser irradiation (HF-LPLI) provides a new stimulator to trigger cell apoptosis, and it is well known that apoptotic cells provide antigens to effectively trigger recognition by the immune system. In order to investigate the effect of HF-LPLI on the professional antigen-presenting cell (APC) function, in our primary study, we focused our attention on the effect of HF-LPLI-treated tumor cells on macrophages phagocytosis and NO production. Both confocal microscopy and flowcytometry analysis showed that HF-LPLI (120 J/cm2) induced significantly EMT6 death. Further experiments showed that HF-LPLI-treated EMT6 cells could be phagocyted by the murine macrophage cells RAW264.7, and could induce NO production in macrophages. Taken together, our results indicate that HF-LPLI-treated tumor cells effectively regulated the immune system. The HF-LPLI effect on the APC function needs to be further studied.

Lu, Cuixia; Zhou, Feifan; Wu, Shengnan; Xing, Da

2013-02-01

83

Macrophage PTEN Regulates Expression and Secretion of Arginase I Modulating Innate and Adaptive Immune Responses  

PubMed Central

The activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN?/? macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBP? and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity. PMID:25015834

Sahin, Emine; Haubenwallner, Stefan; Kuttke, Mario; Kollmann, Isabella; Halfmann, Angela; Dohnal, Alexander B.; Chen, Li; Cheng, Paul; Hoesel, Bastian; Einwallner, Elisa; Brunner, Julia; Kral, Julia B.; Schrottmaier, Waltraud C.; Thell, Kathrin; Saferding, Victoria; Blüml, Stephan

2014-01-01

84

Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses  

PubMed Central

Background Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. Aim To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses. Methodology and principal findings Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-?, IL-13 and IL-10). IFN-? responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner. Conclusions and significance Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients. PMID:25275395

Venugopal, Gopinath; Rao, Gopala B.; Lucius, Richard; Srikantam, Aparna; Hartmann, Susanne

2014-01-01

85

Helical Carbon Nanotubes Enhance the Early Immune Response and Inhibit Macrophage-Mediated Phagocytosis of Pseudomonas aeruginosa  

PubMed Central

Aerosolized or aspirated manufactured carbon nanotubes have been shown to be cytotoxic, cause pulmonary lesions, and demonstrate immunomodulatory properties. CD-1 mice were used to assess pulmonary toxicity of helical carbon nanotubes (HCNTs) and alterations of the immune response to subsequent infection by Pseudomonas aeruginosa in mice. HCNTs provoked a mild inflammatory response following either a single exposure or 2X/week for three weeks (multiple exposures) but were not significantly toxic. Administering HCNTs 2X/week for three weeks resulted in pulmonary lesions including granulomas and goblet cell hyperplasia. Mice exposed to HCNTs and subsequently infected by P. aeruginosa demonstrated an enhanced inflammatory response to P. aeruginosa and phagocytosis by alveolar macrophages was inhibited. However, clearance of P. aeruginosa was not affected. HCNT exposed mice depleted of neutrophils were more effective in clearing P. aeruginosa compared to neutrophil-depleted control mice, accompanied by an influx of macrophages. Depletion of systemic macrophages resulted in slightly inhibited bacterial clearance by HCNT treated mice. Our data indicate that pulmonary exposure to HCNTs results in lesions similar to those caused by other nanotubes and pre-exposure to HCNTs inhibit alveolar macrophage phagocytosis of P. aeruginosa. However, clearance was not affected as exposure to HCNTs primed the immune system for an enhanced inflammatory response to pulmonary infection consisting of an influx of neutrophils and macrophages. PMID:24324555

Walling, Brent E.; Kuang, Zhizhou; Hao, Yonghua; Estrada, David; Wood, Joshua D.; Lian, Feifei; Miller, Lou Ann; Shah, Amish B.; Jeffries, Jayme L.; Haasch, Richard T.; Lyding, Joseph W.; Pop, Eric; Lau, Gee W.

2013-01-01

86

Macrophages: supportive cells for tissue repair and regeneration Short title: Macrophages in tissue repair and regeneration  

E-print Network

1 Macrophages: supportive cells for tissue repair and regeneration Short title: Macrophages cells ­ Regeneration ­ Repair ­ Resolution of inflammation Abbreviations 2-acetylaminofluorene (2-AAF cells, including stem and progenitor cell, of which they regulate the fate. In the present review, few

Paris-Sud XI, Université de

87

Host response. Inflammation-induced disruption of SCS macrophages impairs B cell responses to secondary infection.  

PubMed

The layer of macrophages at the subcapsular sinus (SCS) captures pathogens entering the lymph node, preventing their global dissemination and triggering an immune response. However, how infection affects SCS macrophages remains largely unexplored. Here we show that infection and inflammation disrupt the organization of SCS macrophages in a manner that involves the migration of mature dendritic cells to the lymph node. This disrupted organization reduces the capacity of SCS macrophages to retain and present antigen in a subsequent secondary infection, resulting in diminished B cell responses. Thus, the SCS macrophage layer may act as a sensor or valve during infection to temporarily shut down the lymph node to further antigenic challenge. This shutdown may increase an organism's susceptibility to secondary infections. PMID:25657250

Gaya, Mauro; Castello, Angelo; Montaner, Beatriz; Rogers, Neil; Reis e Sousa, Caetano; Bruckbauer, Andreas; Batista, Facundo D

2015-02-01

88

The role of macrophages and dendritic cells in the initiation of inflammation in IBD  

PubMed Central

In the healthy gastrointestinal tract, homeostasis is an active process that requires a careful balance of host responses to the enteric luminal contents. Intestinal macrophages and dendritic cells comprise a unique group of tissue immune cells that are ideally situated at the interface of the host and the enteric luminal environment to appropriately respond to microbes and ingested stimuli. However, intrinsic defects in macrophage and dendritic cell function contribute to the pathogenesis of inflammatory bowel diseases (IBD), as highlighted by recent genome-wide association studies. Gastrointestinal macrophages and dendritic cells participate in IBD development through inappropriate responses to enteric microbial stimuli, inefficient clearance of microbes from host tissues, and impaired transition from appropriate pro-inflammatory responses to anti-inflammatory responses that promote resolution. By understanding how intestinal macrophages and dendritic cells initiate chronic inflammation, new pathogenesis-based therapeutic strategies to treat human IBD will be elucidated. PMID:23974993

Steinbach, Erin C.; Plevy, Scott E.

2014-01-01

89

Novel insights into the immunomodulatory role of the dendritic cell and macrophage-expressed C-type lectin MGL.  

PubMed

Based on their ability to balance tolerance and inflammation, antigen presenting cells, such as dendritic cells and macrophages contribute to the maintenance of immune homeostasis as well as the instigation of immune activation. Acting as key sensors of tissue integrity and pathogen invasion, they are well equipped with a wide variety of pattern recognition receptors, to which the C-type lectin family also belongs. C-type lectins are glycan-binding receptors that mediate cell-cell communication and pathogen recognition, besides participating in the endocytosis of antigens for presentation to T cells and the fine-tuning of immune responses. Here we review the current state-of-the-art on the dendritic cell and macrophage-expressed C-type lectin macrophage galactose-type lectin (MGL), highlighting the binding specificities, signaling properties and modulation of innate and adaptive immunity by its human and murine orthologues. PMID:25454488

van Kooyk, Yvette; Ilarregui, Juan M; van Vliet, Sandra J

2015-02-01

90

T Cell–Mediated Host Immune Defenses in the Lung  

PubMed Central

Evidence has increasingly shown that the lungs are a major site of immune regulation. A robust and highly regulated immune response in the lung protects the host from pathogen infection, whereas an inefficient or deleterious response can lead to various pulmonary diseases. Many cell types, such as epithelial cells, dendritic cells, macrophages, neutrophils, eosinophils, and B and T lymphocytes, contribute to lung immunity. This review focuses on the recent advances in understanding how T lymphocytes mediate pulmonary host defenses against bacterial, viral, and fungal pathogens. PMID:23516986

Chen, Kong; Kolls, Jay K.

2014-01-01

91

Fc? receptor profile of monocytes and macrophages from rheumatoid arthritis patients and their response to immune complexes formed with autoantibodies to citrullinated proteins  

Microsoft Academic Search

ObjectiveTo analyse Fc? receptor (Fc?R) expression on monocytes and macrophages from rheumatoid arthritis (RA) patients versus healthy controls (HC), and to compare their responses to immune complexes containing RA-specific anti-citrullinated proteins auto antibodies (ACPA).MethodsMonocytes and monocyte-derived macrophages were obtained from the peripheral blood of 34 RA patients and 69 HC. Fc?R expression was studied by flow cytometry. Cells were stimulated

Lætitia Laurent; Cyril Clavel; Olivia Lemaire; Florence Anquetil; Martin Cornillet; Laurent Zabraniecki; Leonor Nogueira; Bernard Fournié; Guy Serre; Mireille Sebbag

2011-01-01

92

A combined omics study on activated macrophages—enhanced role of STATs in apoptosis, immunity and lipid metabolism  

PubMed Central

Background: Macrophage activation by lipopolysaccharide and adenosine triphosphate (ATP) has been studied extensively because this model system mimics the physiological context of bacterial infection and subsequent inflammatory responses. Previous studies on macrophages elucidated the biological roles of caspase-1 in post-translational activation of interleukin-1? and interleukin-18 in inflammation and apoptosis. However, the results from these studies focused only on a small number of factors. To better understand the host response, we have performed a high-throughput study of Kdo2-lipid A (KLA)-primed macrophages stimulated with ATP. Results: The study suggests that treating mouse bone marrow-derived macrophages with KLA and ATP produces ‘synergistic’ effects that are not seen with treatment of KLA or ATP alone. The synergistic regulation of genes related to immunity, apoptosis and lipid metabolism is observed in a time-dependent manner. The synergistic effects are produced by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and activator protein (AP)-1 through regulation of their target cytokines. The synergistically regulated cytokines then activate signal transducer and activator of transcription (STAT) factors that result in enhanced immunity, apoptosis and lipid metabolism; STAT1 enhances immunity by promoting anti-microbial factors; and STAT3 contributes to downregulation of cell cycle and upregulation of apoptosis. STAT1 and STAT3 also regulate glycerolipid and eicosanoid metabolism, respectively. Further, western blot analysis for STAT1 and STAT3 showed that the changes in transcriptomic levels were consistent with their proteomic levels. In summary, this study shows the synergistic interaction between the toll-like receptor and purinergic receptor signaling during macrophage activation on bacterial infection. Availability: Time-course data of transcriptomics and lipidomics can be queried or downloaded from http://www.lipidmaps.org. Contact: shankar@ucsd.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23981351

Dinasarapu, Ashok Reddy; Gupta, Shakti; Ram Maurya, Mano; Fahy, Eoin; Min, Jun; Sud, Manish; Gersten, Merril J.; Glass, Christopher K.; Subramaniam, Shankar

2013-01-01

93

Biomarkers of CD4+ CTL cell Mediated Immunity to Tuberculosis  

Technology Transfer Automated Retrieval System (TEKTRAN)

The immune responses mediated by interactions between T-lymphocyte subsets and mycobacteria-infected macrophages are critical for control of tuberculosis. In these studies, the bovine model was used to characterize the cytolytic and mycobactericidal CD4+ T cell response induced by BCG vaccination. ...

94

Macrophage and T Cell Produced IL-10 Promotes Viral Chronicity  

PubMed Central

Chronic viral infections lead to CD8+ T cell exhaustion, characterized by impaired cytokine secretion. Presence of the immune-regulatory cytokine IL-10 promotes chronicity of Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 infection, while absence of IL-10/IL-10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine producing T cells. IL-10 is produced by several cell types during LCMV infection but it is currently unclear which cellular sources are responsible for induction of viral chronicity. Here, we demonstrate that although dendritic cells produce IL-10 and overall IL-10 mRNA levels decrease significantly in absence of CD11c+ cells, absence of IL-10 produced by CD11c+ cells failed to improve the LCMV-specific T cell response and control of LCMV infection. Similarly, NK cell specific IL-10 deficiency had no positive impact on the LCMV-specific T cell response or viral control, even though high percentages of NK cells produced IL-10 at early time points after infection. Interestingly, we found markedly improved T cell responses and clearance of normally chronic LCMV Clone 13 infection when either myeloid cells or T cells lacked IL-10 production and mice depleted of monocytes/macrophages or CD4+ T cells exhibited reduced overall levels of IL-10 mRNA. These data suggest that the decision whether LCMV infection becomes chronic or can be cleared critically depends on early CD4+ T cell and monocyte/macrophage produced IL-10. PMID:24244162

Richter, Kirsten; Perriard, Guillaume; Behrendt, Rayk; Schwendener, Reto A.; Sexl, Veronika; Dunn, Robert; Kamanaka, Masahito; Flavell, Richard A.; Roers, Axel; Oxenius, Annette

2013-01-01

95

CpG and LPS can interfere negatively with prion clearance in macrophage and microglial cells.  

PubMed

Cells of the innate immune system play important roles in the progression of prion disease after peripheral infection. It has been found in vivo and in vitro that the expression of the cellular prion protein (PrP(c)) is up-regulated on stimulation of immune cells, also indicating the functional importance of PrP(c) in the immune system. The aim of our study was to investigate the impact of cytosine-phosphate-guanosine- and lipopolysaccharide-induced PrP(c) up-regulation on the uptake and processing of the pathological prion protein (PrP(Sc)) in phagocytic innate immune cells. For this purpose, we challenged the macrophage cell line J774, the microglial cell line BV-2 and primary bone marrow-derived macrophages in a resting or stimulated state with various prion strains, and monitored the uptake and clearance of PrP(Sc). Interestingly, stimulation led either to a transient increase in the level of PrP(Sc) relative to unstimulated cells or to a decelerated degradation of PrP(Sc). These features were dependent on cell type and prion strain. Our data indicate that the stimulation of innate immune cells may be able to support transient prion propagation, possibly explained by an increased PrP(c) cell surface expression in stimulated cells. We suggest that stimulation of innate immune cells can lead to an imbalance between the propagation and degradation of PrP(Sc). PMID:17944938

Gilch, Sabine; Schmitz, Frank; Aguib, Yasmine; Kehler, Claudia; Bülow, Sigrid; Bauer, Stefan; Kremmer, Elisabeth; Schätzl, Hermann M

2007-11-01

96

Selective Early Production of CCL20, or Macrophage Inflammatory Protein 3 , by Human Mast Cells in Response to Pseudomonas aeruginosa  

Microsoft Academic Search

Mast cells are important as sentinel cells in host defense against bacterial infection. Much of their effectiveness depends upon recruiting other immune cells; however, little is known about the mechanisms of this response. CCL20, also known as macrophage inflammatory protein-3 (MIP-3), Exodus, and LARC, is a chemokine known to be a potent chemoattractant for immature dendritic cells and T cells.

Tong-Jun Lin; Lauren H. Maher; Kaede Gomi; Jeffrey D. McCurdy; Rafael Garduno; Jean S. Marshall

2003-01-01

97

Lymph node macrophages  

PubMed Central

Summary Lymph node (LN) macrophages have long been known for their efficient uptake of lymph-borne antigens. A convergence of studies on innate and adaptive immune responses has led to exciting recent advances in understanding their more specialized properties: presenting antigens to B cells, dendritic cells and T cells, producing trophic factors and cytokines, and, remarkably, being permissive for viral infection, a property critical for mounting anti-viral responses. LN macrophages have been traditionally divided into subsets based on their subcapsular sinus and medullary locations. Here we classify LN macrophages into three subsets: subcapsular sinus macrophages (SSMs), medullary sinus macrophages (MSMs) and medullary cord macrophages (MCMs). We review the literature regarding the roles of these cells in innate and adaptive immune responses and requirements for their development. We also discuss challenges associated with their purification as well as the existence of additional heterogeneity among LN macrophages. PMID:22488251

Gray, Elizabeth E.; Cyster, Jason G.

2013-01-01

98

Proteomic analysis and immune properties of exosomes released by macrophages infected with Mycobacterium avium.  

PubMed

The role of exosomes shed from Mycobacterium avium sp. paratuberculosis-infected macrophages in intercellular communication processes was examined. We compared the responses of resting macrophages infected with M. avium sp. paratuberculosis with those of resting macrophages treated with exosomes previously released from macrophages infected with M. avium sp. paratuberculosis. Some proteins components of exosomes released from resting macrophages infected with M. avium sp. paratuberculosis showed a significantly differential expression compared with exosomes from uninfected-macrophages. Both M. avium sp. paratuberculosis and exosomes from infected-cells enhanced the expression of CD80 and CD86 and the secretion of TNF-? and IFN-? by macrophages. This suggests that exosomes from infected macrophages may be carriers of molecules, e.g. bacterial antigens and/or components from infected macrophages, that can elicit responses in resting cells. Two-dimensional analysis of the proteins present in exosomes from M. avium sp. paratuberculosis-infected macrophages compared with those from resting cells resulted in the identification by MALDI-TOF/TOF mass spectrometry of the following differentially expressed proteins: two actin isoforms, guanine nucleotide-binding protein ?-1, cofilin-1 and peptidyl-prolyl cis-trans isomerase A. The possible relevance of the changes observed and the biological functions of the proteins differentially present are discussed. PMID:24355714

Wang, Jian-jun; Chen, Cai; Xie, Ping-fang; Pan, Yi; Tan, Yun-hong; Tang, Li-jun

2014-04-01

99

Macrophage-tumor cell interactions regulate the function of nitric oxide  

PubMed Central

Tumor cell-macrophage interactions change as the tumor progresses, and the generation of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS) plays a major role in this interplay. In early stages, macrophages employ their killing mechanisms, particularly the generation of high concentrations of NO and its derivative reactive nitrogen species (RNS) to initiate tumor cell apoptosis and destroy emerging transformed cells. If the tumor escapes the immune system and grows, macrophages that infiltrate it are reprogramed in situ by the tumor microenvironment. Low oxygen tensions (hypoxia) and immunosuppressive cytokines inhibit iNOS activity and lead to production of low amounts of NO/RNS, which are pro-angiogenic and support tumor growth and metastasis by inducing growth factors (e.g., VEGF) and matrix metalloproteinases (MMPs). We review here the different roles of NO/RNS in tumor progression and inhibition, and the mechanisms that regulate iNOS expression and NO production, highlighting the role of different subtypes of macrophages and the microenvironment. We finally claim that some tumor cells may become resistant to macrophage-induced death by increasing their expression of microRNA-146a (miR-146a), which leads to inhibition of iNOS translation. This implies that some cooperation between tumor cells and macrophages is required to induce tumor cell death, and that tumor cells may control their fate. Thus, in order to induce susceptibility of tumors cells to macrophage-induced death, we suggest a new therapeutic approach that couples manipulation of miR-146a levels in tumors with macrophage therapy, which relies on ex vivo stimulation of macrophages and their re-introduction to tumors. PMID:23785333

Rahat, Michal A.; Hemmerlein, Bernhard

2013-01-01

100

Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection  

PubMed Central

Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2?/? macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2?/? macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-?) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2?/? macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages PMID:23630227

Nairz, Manfred; Schleicher, Ulrike; Schroll, Andrea; Sonnweber, Thomas; Theurl, Igor; Ludwiczek, Susanne; Talasz, Heribert; Brandacher, Gerald; Moser, Patrizia L.; Muckenthaler, Martina U.; Fang, Ferric C.; Bogdan, Christian

2013-01-01

101

Emerging themes in IFN-?-induced macrophage immunity by the p47 and p65 GTPase Families  

PubMed Central

Vertebrates have evolved complex immune specificity repertoires beyond the primordial components found in lower multi-cellular organisms to combat microbial infections. The type II interferon (IFN-?) pathway represents one such system, bridging innate and acquired immunity and providing host protection in a cell-autonomous manner. Recent large-scale transcriptome analyses of IFN-?-dependent gene expression in effector cells such as macrophages have highlighted the prominence of two families of GTPases - p47 IRGs and p65 GBPs – that are now beginning to emerge as major determinants of antimicrobial resistance. Here we discuss the recent clarification of known family members, their cellular biochemistry and host defense functions as a means to understanding the complex innate immune response engendered in higher vertebrates such as humans and mice. PMID:18086378

Shenoy, Avinash R.; Kim, Bae-Hoon; Choi, Han-Pil; Matsuzawa, Takeshi; Tiwari, Sangeeta; MacMicking, John D.

2009-01-01

102

Cell death and DNA damage in peritoneal macrophages of mice ( Mus musculus) exposed to inorganic lead  

Microsoft Academic Search

Lead is a heavy metal of considerable environmental and occupational concern and there is growing evidence that it is toxic to the human immune system. In this regard, this study examined the effect of lead (Pb) exposure to peritoneal macrophages (M?s) of mice (Mus musculus) cultivated in DMEM medium supplemented with fetal bovine serum, in order to investigate cell damage

R. Gargioni; F. Filipak Neto; D. F. Buchi; M. A. F. Randi; C. R. C. Franco; K. S. Paludo; É. Pelletier; M. V. M. Ferraro; M. M. Cestari; D. Bussolaro; C. A. Oliveira Ribeiro

2006-01-01

103

NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein  

PubMed Central

To subvert host immunity, influenza A virus (IAV) induces early apoptosis in innate immune cells by disrupting mitochondria membrane potential via its polymerase basic protein 1-frame 2 (PB1-F2) accessory protein. Whether immune cells have mechanisms to counteract PB1-F2–mediated apoptosis is currently unknown. Herein, we define that the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 binds to viral protein PB1-F2, preventing IAV-induced macrophage apoptosis and promoting both macrophage survival and type I IFN signaling. We initially observed that Nlrx1-deficient mice infected with IAV exhibited increased pulmonary viral replication, as well as enhanced inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly enhanced leukocyte recruitment but impaired production of type I IFN in Nlrx1?/? mice. Impaired type I IFN production and enhanced viral replication was recapitulated in Nlrx1?/? macrophages and was associated with increased mitochondrial mediated apoptosis. Through gain- and loss-of-function strategies for protein interaction, we identified that NLRX1 directly bound PB1-F2 in the mitochondria of macrophages. Using a recombinant virus lacking PB1-F2, we confirmed that deletion of PB1-F2 abrogated NLRX1-dependent macrophage type I IFN production and apoptosis. Thus, our results demonstrate that NLRX1 acts as a mitochondrial sentinel protecting macrophages from PB1-F2–induced apoptosis and preserving their antiviral function. We further propose that NLRX1 is critical for macrophage immunity against IAV infection by sensing the extent of viral replication and maintaining a protective balance between antiviral immunity and excessive inflammation within the lungs. PMID:24799673

Jaworska, Joanna; Coulombe, François; Downey, Jeffrey; Tzelepis, Fanny; Shalaby, Karim; Tattoli, Ivan; Berube, Julie; Rousseau, Simon; Martin, James G.; Girardin, Stephen E.; McCullers, Jonathan A.; Divangahi, Maziar

2014-01-01

104

Neutrophils and macrophages work in concert as inducers and effectors of adaptive immunity against extracellular and intracellular microbial pathogens  

Microsoft Academic Search

Emerging data suggest new facets of the concerted participation of neutrophils and macrophages in antimi- crobial immunity. The classical view is that DCs and macrophages are the inducers of adaptive antimicro- bial immunity, but there is evidence for neutrophil par- ticipation in this task as cytokine and chemokine pro- ducers and APCs. On the other hand, the concept that the

Manuel T. Silva

2010-01-01

105

Cells of the synovium in rheumatoid arthritis. Macrophages  

PubMed Central

The multitude and abundance of macrophage-derived mediators in rheumatoid arthritis and their paracrine/autocrine effects identify macrophages as local and systemic amplifiers of disease. Although uncovering the etiology of rheumatoid arthritis remains the ultimate means to silence the pathogenetic process, efforts in understanding how activated macrophages influence disease have led to optimization strategies to selectively target macrophages by agents tailored to specific features of macrophage activation. This approach has two advantages: (a) striking the cell population that mediates/amplifies most of the irreversible tissue destruction and (b) sparing other cells that have no (or only marginal) effects on joint damage. PMID:18177511

Kinne, Raimund W; Stuhlmüller, Bruno; Burmester, Gerd-R

2007-01-01

106

Differential Transcriptional Response in Macrophages Infected with Cell Wall Deficient versus Normal Mycobacterium Tuberculosis.  

PubMed

Host-pathogen interactions determine the outcome following infection by mycobacterium tuberculosis (Mtb). Under adverse circumstances, normal Mtb can form cell-wall deficient (CWD) variants within macrophages, which have been considered an adaptive strategy for facilitating bacterial survival inside macrophages. However, the molecular mechanism by which infection of macrophages with different phenotypic Mtb elicits distinct responses of macrophages is not fully understood. To explore the molecular events triggered upon Mtb infection of macrophages, differential transcriptional responses of RAW264.7 cells infected with two forms of Mtb, CWD-Mtb and normal Mtb, were studied by microarray analysis. Some of the differentially regulated genes were confirmed by RT-qPCR in both RAW264.7 cells and primary macrophages. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was used to analyze functions of differentially expressed genes. Distinct gene expression patterns were observed between CWD-Mtb and normal Mtb group. Mapt was up-regulated, while NOS2 and IL-11 were down-regulated in CWD-Mtb infected RAW264.7 cells and primary macrophages compared with normal Mtb infected ones. Many deregulated genes were found to be related to macrophages activation, immune response, phagosome maturation, autophagy and lipid metabolism. KEGG analysis showed that the differentially expressed genes were mainly involved in MAPK signaling pathway, nitrogen metabolism, cytokine-cytokine receptor interaction and focal adhesion. Taken together, the present study showed that differential macrophage responses were induced by intracellular CWD-Mtb an normal Mtb infection, which suggested that interactions between macrophages and different phenotypic Mtb are very complex. The results provide evidence for further understanding of pathogenesis of CWD-Mtb and may help in improving strategies to eliminate intracellular CWD-Mtb. PMID:25552926

Fu, Yu-Rong; Gao, Kun-Shan; Ji, Rui; Yi, Zheng-Jun

2015-01-01

107

Differential Transcriptional Response in Macrophages Infected with Cell Wall Deficient versus Normal Mycobacterium Tuberculosis  

PubMed Central

Host-pathogen interactions determine the outcome following infection by mycobacterium tuberculosis (Mtb). Under adverse circumstances, normal Mtb can form cell-wall deficient (CWD) variants within macrophages, which have been considered an adaptive strategy for facilitating bacterial survival inside macrophages. However, the molecular mechanism by which infection of macrophages with different phenotypic Mtb elicits distinct responses of macrophages is not fully understood. To explore the molecular events triggered upon Mtb infection of macrophages, differential transcriptional responses of RAW264.7 cells infected with two forms of Mtb, CWD-Mtb and normal Mtb, were studied by microarray analysis. Some of the differentially regulated genes were confirmed by RT-qPCR in both RAW264.7 cells and primary macrophages. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was used to analyze functions of differentially expressed genes. Distinct gene expression patterns were observed between CWD-Mtb and normal Mtb group. Mapt was up-regulated, while NOS2 and IL-11 were down-regulated in CWD-Mtb infected RAW264.7 cells and primary macrophages compared with normal Mtb infected ones. Many deregulated genes were found to be related to macrophages activation, immune response, phagosome maturation, autophagy and lipid metabolism. KEGG analysis showed that the differentially expressed genes were mainly involved in MAPK signaling pathway, nitrogen metabolism, cytokine-cytokine receptor interaction and focal adhesion. Taken together, the present study showed that differential macrophage responses were induced by intracellular CWD-Mtb an normal Mtb infection, which suggested that interactions between macrophages and different phenotypic Mtb are very complex. The results provide evidence for further understanding of pathogenesis of CWD-Mtb and may help in improving strategies to eliminate intracellular CWD-Mtb. PMID:25552926

Fu, Yu-Rong; Gao, Kun-Shan; Ji, Rui; Yi, Zheng-Jun

2015-01-01

108

The macrophage-TCR?? is a cholesterol-responsive combinatorial immune receptor and implicated in atherosclerosis.  

PubMed

Recent evidence indicates constitutive expression of a recombinatorial TCR?? immune receptor in mammalian monocytes and macrophages. Here, we demonstrate in vitro that macrophage-TCR? repertoires are modulated by atherogenic low density cholesterol (LDL) and high-density cholesterol (HDL). In vivo, analysis of freshly obtained artery specimens from patients with severe carotid atherosclerosis reveals massive abundance of TCR??(+) macrophages within the atherosclerotic lesions. Experimental atherosclerosis in mouse carotids induces accumulation of TCR bearing macrophages in the vascular wall and TCR deficient rag(-/-) mice have an altered macrophage-dependent inflammatory response. We find that the majority of TCR?? bearing macrophages are localized in the hot spot regions of the atherosclerotic lesions. Advanced carotid artery lesions express highly restricted TCR?? repertoires that are characterized by a striking usage of the V?22 and V?16 chains. This together with a significant degree of interindividual lesion repertoire sharing suggests the existence of atherosclerosis-associated TCR?? signatures. Our results implicate the macrophage-TCR?? combinatorial immunoreceptor in atherosclerosis and thus identify an as yet unknown adaptive component in the innate response-to-injury process that underlies this macrophage-driven disease. PMID:25446098

Fuchs, Tina; Puellmann, Kerstin; Emmert, Alexander; Fleig, Julian; Oniga, Septimia; Laird, Rebecca; Heida, Nana Maria; Schäfer, Katrin; Neumaier, Michael; Beham, Alexander W; Kaminski, Wolfgang E

2015-01-01

109

Tumour-educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion.  

PubMed

At the time of diagnosis, almost 80% of pancreatic cancer patients present with new-onset type 2 diabetes (T2D) or impaired glucose tolerance. T2D and pancreatic cancer are both associated with low-grade inflammation. Tumour-associated macrophages (TAMs) have a key role in cancer-related inflammation, immune escape, matrix remodelling and metastasis. In this study, the interplay between tumour cells and immune cells under the influence of different glucose levels was investigated. Human peripheral blood mononuclear cells were exposed in vitro to conditioned medium from BxPC-3 human pancreatic cancer cells, in normal (5 mM) or high (25 mM) glucose levels. Flow cytometry analyses demonstrated that tumour-derived factors stimulated differentiation of macrophages, with a mixed classical (M1-like) and alternatively activated (M2-like) phenotype polarisation (CD11c(+)CD206(+)). High-glucose conditions further enhanced the tumour-driven macrophage enrichment and associated interleukin (IL)-6 and IL-8 cytokine levels. In addition, hyperglycaemia enhanced the responsiveness of tumour-educated macrophages to lipopolysaccharide, with elevated cytokine secretion compared with normal glucose levels. Tumour-educated macrophages were found to promote pancreatic cancer cell invasion in vitro, which was significantly enhanced at high glucose. The anti-diabetic drug metformin shifted the macrophage phenotype polarisation and reduced the tumour cell invasion at normal, but not high, glucose levels. In conclusion, this study demonstrates that pancreatic cancer cells stimulate differentiation of macrophages with pro-tumour properties that are further enhanced by hyperglycaemia. These findings highlight important crosstalk between tumour cells and TAMs in the local tumour microenvironment that may contribute to disease progression in pancreatic cancer patients with hyperglycaemia and T2D. PMID:24662521

Karnevi, Emelie; Andersson, Roland; Rosendahl, Ann H

2014-07-01

110

Regulatory T cells and innate immune regulation in tumor immunity  

Microsoft Academic Search

Innate and adaptive immunity play important roles in immunosurveillance and tumor destruction. However, increasing evidence suggests that tumor-infiltrating immune cells may have a dual function: inhibiting or promoting tumor growth and progression. Although regulatory T (Treg) cells induce immune tolerance by suppressing host immune responses against self- or nonself-antigens, thus playing critical roles in preventing autoimmune diseases, they might inhibit

Rong-Fu Wang

2006-01-01

111

Osteogenesis differentiation of human periodontal ligament cells by CO2 laser-treatment stimulating macrophages via BMP2 signalling pathway  

NASA Astrophysics Data System (ADS)

Immune reactions play an important role in determining the biostimulation of bone formation, either in new bone formation or inflammatory fibrous tissue encapsulation. Macrophage cell, the important effector cells in the immune reaction, which are indispensable for osteogenesis and their heterogeneity and plasticity, render macrophages a primer target for immune system modulation. However, there are very few studies about the effects of macrophage cells on laser treatment-regulated osteogenesis. In this study, we used CO2 laser as a model biostimulation to investigate the role of macrophage cells on the CO2 laser stimulated osteogenesis. Bone morphogenetic protein 2 (BMP2) was also significantly up regulated by the CO2 laser stimulation, indicating that macrophage may participate in the CO2 laser stimulated osteogenesis. Interestingly, when laser treatment macrophage-conditioned medium were applied to human periodontal ligament cells (hPDLs), the osteogenesis differentiation of hPDLs was significantly enhanced, indicating the important role of macrophages in CO2 laser-induced osteogenesis. These findings provided valuable insights into the mechanism of CO2 laser-stimulated osteogenic differentiation, and a strategy to optimize the evaluation system for the in vitro osteogenesis capacity of laser treatment.

Hsieh, Wen-Hui; Chen, Yi-Jyun; Hung, Chi-Jr; Huang, Tsui-Hsien; Kao, Chia-Tze; Shie, Ming-You

2014-11-01

112

Chemical characterization of specific pulmonary macrophage cell surface antigen  

Microsoft Academic Search

Pulmonary macrophages of mice have a unique cell surface antigen not shared by other cell types. In the study reported here,\\u000a the cell surface proteins of pulmonary macrophages were labeled with125I, dissociated by the detergent NP-40, and reacted with either specific guinea pig anti-mouse pulmonary macrophage serum or\\u000a normal guinea pig serum. Goat anti-guinea pig IgG was used for immunoprecipitation,

John J. Godleski; M. Anwar Joher; Jeffrey D. Goldstein; Joseph D. Brain

1984-01-01

113

Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG  

Microsoft Academic Search

Hosts infected with low doses of myco- bacteria develop T helper cell type 1 (Th1) immu- nity, but at relatively higher doses, a switch to Th2 immunity occurs. Prostaglandin E2 (PGE2) is a pro- posed mediator of the Th1-to-Th2 shift of immune responses, and mycobacterial products induce PGE2- releasing macrophages (PGE2-MA) in the mouse spleen in a dose-dependent manner. Splenic

Yoshimi Shibata; Ruth Ann Henriksen; Ikuro Honda; Reiko M. Nakamura; Quentin N. Myrvik

2005-01-01

114

Immune cell promotion of metastasis.  

PubMed

Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Data from mouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells. PMID:25614318

Kitamura, Takanori; Qian, Bin-Zhi; Pollard, Jeffrey W

2015-01-23

115

Proportion of infiltrating IgG-binding immune cells predict for tumour hypoxia  

PubMed Central

Macrophages can account for up to 50% of tumour mass and secrete many angiogenic factors. Furthermore, tumour hypoxia is thought to play a major role in the activation of macrophages and the regulation of angiogenesis. In this paper, we demonstrate a strong correlation between hypoxia and the recruitment of immune cells binding to IgG in 8 experimental tumours. We provide evidence that IgG binding immune cells in 3 tumour lines are predominately composed of macrophages. Reduced oxygenation may act as a stimulus for recruitment of immune cells to the tumour mass, and the detection of either IgG-positive host cells or macrophages may offer an alternative method for monitoring tumour hypoxia. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11237382

Collingridge, D R; Hill, S A; Chaplin, D J

2001-01-01

116

Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction.  

PubMed

Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3 days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M1 and M2 macrophages, respectively, based on surface-marker expression. M1 macrophages dominated at 1-3 days post-MI, whereas M2 macrophages represented the predominant macrophage subset after 5 days. The M2 macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M1 macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4(+) T cells, whereas Th2 and Th17 cells were minor populations. CD8(+) T cells, ??T cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post-MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies. PMID:23644221

Yan, Xiaoxiang; Anzai, Atsushi; Katsumata, Yoshinori; Matsuhashi, Tomohiro; Ito, Kentaro; Endo, Jin; Yamamoto, Tsunehisa; Takeshima, Akiko; Shinmura, Ken; Shen, Weifeng; Fukuda, Keiichi; Sano, Motoaki

2013-09-01

117

Improved Method for Culturing Guinea-Pig Macrophage Cells  

NASA Technical Reports Server (NTRS)

Proper nutrients and periodic changes in culture medium maintain cell viability for a longer period. New method uses a thioglycolate solution, instead of mineral oil, to induce macrophage cells in guinea pigs and also uses an increased percent of fetal-calf bovine serum in cultivation medium. Macrophage cells play significant roles in the body's healing and defense systems.

Savage, J.

1982-01-01

118

Murine macrophage inflammatory cytokine production and immune activation in response to Vibrio parahaemolyticus infection  

Technology Transfer Automated Retrieval System (TEKTRAN)

Vibrio parahaemolyticus is the most common cause of bacterial seafood-related illness in the United States. Currently, there is a dearth of literature regarding immunity to infection with this pathogen. Here we studied V. parahaemolyticus-infected RAW 264.7 murine macrophage detecting both pro- and...

119

Streptolysin O Promotes Group A Streptococcus Immune Evasion by Accelerated Macrophage Apoptosis*  

E-print Network

Streptolysin O Promotes Group A Streptococcus Immune Evasion by Accelerated Macrophage Apoptosis and §§ Department of Biology, San Diego State University, San Diego, California 92182 Group A Streptococcus (GAS A Streptococcus (GAS)4 is a leading human pathogen that annually infects hundreds of millions of people worldwide

Nizet, Victor

120

PHAGOCYTOSIS OF IMMUNE C OMPLEXES BY MACROPHAGES DIFFERENT ROLES O12\\  

Microsoft Academic Search

The relative roles of the above immune factors in particle attachment and inges- tion have not been adequately examined. In this paper we describe a quantita- tive technique which permits a separate evaluation of these two successive stages of phagocytosis. This technique was used to study the encounter of mouse peritoneal macrophages with sheep erythrocytes (E) ~ coated with either

B. MANTOVANI; M. RABINOVITCH; V. NUSSENZWEIG

121

Inflammatory Mechanisms in sepsis: Elevated Invariant Natural Killer T-cell numbers in mouse and their modulatory effect on Macrophage function  

PubMed Central

Invariant Natural Killer T-cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. iNKT-cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. iNKT-cells have been shown to modulate various mediators of the innate immune system, including macrophages. Herein we demonstrate sepsis inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by Programmed Death Receptor-1(PD-1). PD-1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT-cells. PD-1 has been associated with markers of human critical illness. PD-1 deficient iNKT-cells failed to demonstrate similar migration. To the extent that iNKT-cells affected peritoneal macrophage function we assessed peritoneal macrophages ability to phagocytose bacteria. iNKT?/? mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT?/? mice were co-cultured with wild type iNKT-cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by PD-1, and these peritoneal iNKT-cells appear critical to regulation of peritoneal macrophage phagocytic function. iNKT-cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis. PMID:23807244

Heffernan, Daithi S.; Monaghan, Sean F.; Thakkar, Rajan K.; Tran, Mai L.; Chung, Chun-Shiang; Gregory, Stephen H.; Cioffi, William G.; Ayala, Alfred

2014-01-01

122

Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function.  

PubMed

Invariant natural killer T cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. Invariant natural killer T cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. Invariant natural killer T cells have been shown to modulate various mediators of the innate immune system, including macrophages. We demonstrate sepsis-inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by programmed death receptor 1. Programmed death receptor 1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT cells. Programmed death receptor 1 has been associated with markers of human critical illness. Programmed death receptor 1-deficient iNKT cells failed to demonstrate similar migration. To the extent that iNKT cells affected peritoneal macrophage function, we assessed peritoneal macrophages' ability to phagocytose bacteria. Invariant natural killer T(-/-) mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT(-/-) mice were cocultured with wild-type iNKT cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by programmed death receptor 1, and these peritoneal iNKT cells appear critical to regulation of peritoneal macrophage phagocytic function. Invariant natural killer T cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis. PMID:23807244

Heffernan, Daithi S; Monaghan, Sean F; Thakkar, Rajan K; Tran, Mai L; Chung, Chun-Shiang; Gregory, Stephen H; Cioffi, William G; Ayala, Alfred

2013-08-01

123

Antagonism by Ganoderma lucidum polysaccharides against the suppression by culture supernatants of B16F10 melanoma cells on macrophage.  

PubMed

It is well-documented that macrophages have the functions to regulate antitumor immune response. Antitumor response can be launched by a series of events, starting with inflammation mediated by monocyte/macrophages, which stimulates natural killer and dendritic cells and finally activates the cytotoxic lymphoid system. Monocytes/macrophages may be the first line of defense in tumors. However, specific and nonspecific immunotherapy for human cancer has shown no success or limited success in clinical trials. Part of the reasons attribute to tumor-derived soluble factors that suppress functions of immune cells or induce apoptosis of these cells, including macrophages. Therefore, antagonism of the suppression on the macrophages is an important goal for tumor immunotherapy. To achieve this purpose, Ganoderma lucidum polysaccharides (Gl-PS) with multiple bioactivities were used on mouse peritoneal macrophages incubating with culture supernatants of B16F10 melanoma cells (B16F10-CS). It was shown that the viability, phagocytic activity, NO production, TNF-? production and activity in peritoneal macrophages after activation by lipopolysaccharide were suppressed by B16F10-CS, while the suppressions were fully or partially antagonized by Gl-PS. In conclusion, B16F10-CS is suppressive to the viability, phagocytic activity, NO production, TNF-? production and activity in peritoneal macrophages while Gl-PS had the antagonistic effects against this suppression, suggesting this potential of Gl-PS to facilitate cancer immunotherapy. PMID:23519930

Lu, Jie; Sun, Li-Xin; Lin, Zhi-Bin; Duan, Xin-Suo; Ge, Zhi-Hua; Xing, En-Hong; Lan, Tian-Fei; Yang, Ning; Li, Xue-Jun; Li, Min; Li, Wei-Dong

2014-02-01

124

Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy  

PubMed Central

Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs), which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative) phenotype. The interaction between tumor cells and macrophages provides opportunities for therapy. This paper will discuss secreted proteins as targets for intervention. PMID:22162712

Baay, Marc; Brouwer, Anja; Pauwels, Patrick; Peeters, Marc; Lardon, Filip

2011-01-01

125

TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells  

PubMed Central

Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80+ lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance. PMID:23149665

Albacker, Lee A; Yu, Sanhong; Bedoret, Denis; Lee, Wan-Ling; Umetsu, Sarah E; Monahan, Sheena; Freeman, Gordon J; Umetsu, Dale T; DeKruyff, Rosemarie H

2014-01-01

126

Differentiation of C2D macrophage cells after adoptive transfer.  

PubMed

C2D macrophage cells protect immunocompromised mice from experimentally induced pneumonias after intraperitoneal (i.p.) adoptive transfer. These macrophage cells are immature and display minimal activity in vitro. Therefore, we wanted to understand how adoptive transfer affected these cells. We believe that the in vivo environment affects the phenotypic and functional characteristics of macrophages that help maintain the physiological integrity of the host. To test this hypothesis, we characterized the trafficking patterns and cellular changes of the established macrophage C2D cell line after adoptive transfer. We examined phenotypic changes of the C2D macrophage cells in vivo with and without stimulation with gamma interferon (IFN-gamma). After in vivo i.p. adoptive transfer, C2D macrophage cells trafficked to the lungs, spleen, lymph nodes, and bone marrow of recipient mice. The cells were detected for as long as 2 months, and the cells expressed increased levels of CD11b, c-fms, and F4/80 on their surface, becoming more differentiated macrophages compared to cells maintained in vitro. Upon in vivo stimulation with IFN-gamma, c-fms levels decreased while Gr-1 levels increased compared to in vivo, unstimulated, phosphate-buffered saline-injected controls. These responses were independent of the genetic backgrounds of the recipient mice. These data support the hypothesis and indicate that C2D macrophage cells respond to in vivo signals that are absent during in vitro culture. PMID:18094115

Potts, Betsey E; Hart, Marcia L; Snyder, Laura L; Boyle, Dan; Mosier, Derek A; Chapes, Stephen K

2008-02-01

127

BK channels in innate immune functions of neutrophils and macrophages  

PubMed Central

Oxygen-dependent antimicrobial activity of human polymorphonuclear leukocytes (PMNs) relies on the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate oxidants. As the oxidase transfers electrons from NADPH the membrane will depolarize and concomitantly terminate oxidase activity, unless there is charge translocation to compensate. Most experimental data implicate proton channels as the effectors of this charge compensation, although large-conductance Ca2+-activated K+ (BK) channels have been suggested to be essential for normal PMN antimicrobial activity. To test this latter notion, we directly assessed the role of BK channels in phagocyte function, including the NADPH oxidase. PMNs genetically lacking BK channels (BK?/?) had normal intracellular and extracellular NADPH oxidase activity in response to both receptor-independent and phagocytic challenges. Furthermore, NADPH oxidase activity of human PMNs and macrophages was normal after treatment with BK channel inhibitors. Although BK channel inhibitors suppressed endotoxin-mediated tumor necrosis factor-? secretion by bone marrow-derived macrophages (BMDMs), BMDMs of BK?/? and wild-type mice responded identically and exhibited the same ERK, PI3K/Akt, and nuclear factor-?B activation. Based on these data, we conclude that the BK channel is not required for NADPH oxidase activity in PMNs or macrophages or for endotoxin-triggered tumor necrosis factor-? release and signal transduction BMDMs. PMID:19074007

Essin, Kirill; Gollasch, Maik; Rolle, Susanne; Weissgerber, Patrick; Sausbier, Matthias; Bohn, Erwin; Autenrieth, Ingo B.; Ruth, Peter; Luft, Friedrich C.; Kettritz, Ralph

2009-01-01

128

Regulation of icam-1 in cells of the monocyte/macrophage system in microgravity.  

PubMed

Cells of the immune system are highly sensitive to altered gravity, and the monocyte as well as the macrophage function is proven to be impaired under microgravity conditions. In our study, we investigated the surface expression of ICAM-1 protein and expression of ICAM-1 mRNA in cells of the monocyte/macrophage system in microgravity during clinostat, parabolic flight, sounding rocket, and orbital experiments. In murine BV-2 microglial cells, we detected a downregulation of ICAM-1 expression in clinorotation experiments and a rapid and reversible downregulation in the microgravity phase of parabolic flight experiments. In contrast, ICAM-1 expression increased in macrophage-like differentiated human U937 cells during the microgravity phase of parabolic flights and in long-term microgravity provided by a 2D clinostat or during the orbital SIMBOX/Shenzhou-8 mission. In nondifferentiated U937 cells, no effect of microgravity on ICAM-1 expression could be observed during parabolic flight experiments. We conclude that disturbed immune function in microgravity could be a consequence of ICAM-1 modulation in the monocyte/macrophage system, which in turn could have a strong impact on the interaction with T lymphocytes and cell migration. Thus, ICAM-1 can be considered as a rapid-reacting and sustained gravity-regulated molecule in mammalian cells. PMID:25654110

Paulsen, Katrin; Tauber, Svantje; Dumrese, Claudia; Bradacs, Gesine; Simmet, Dana M; Gölz, Nadine; Hauschild, Swantje; Raig, Christiane; Engeli, Stephanie; Gutewort, Annett; Hürlimann, Eva; Biskup, Josefine; Unverdorben, Felix; Rieder, Gabriela; Hofmänner, Daniel; Mutschler, Lisa; Krammer, Sonja; Buttron, Isabell; Philpot, Claudia; Huge, Andreas; Lier, Hartwin; Barz, Ines; Engelmann, Frank; Layer, Liliana E; Thiel, Cora S; Ullrich, Oliver

2015-01-01

129

Regulation of ICAM-1 in Cells of the Monocyte/Macrophage System in Microgravity  

PubMed Central

Cells of the immune system are highly sensitive to altered gravity, and the monocyte as well as the macrophage function is proven to be impaired under microgravity conditions. In our study, we investigated the surface expression of ICAM-1 protein and expression of ICAM-1 mRNA in cells of the monocyte/macrophage system in microgravity during clinostat, parabolic flight, sounding rocket, and orbital experiments. In murine BV-2 microglial cells, we detected a downregulation of ICAM-1 expression in clinorotation experiments and a rapid and reversible downregulation in the microgravity phase of parabolic flight experiments. In contrast, ICAM-1 expression increased in macrophage-like differentiated human U937 cells during the microgravity phase of parabolic flights and in long-term microgravity provided by a 2D clinostat or during the orbital SIMBOX/Shenzhou-8 mission. In nondifferentiated U937 cells, no effect of microgravity on ICAM-1 expression could be observed during parabolic flight experiments. We conclude that disturbed immune function in microgravity could be a consequence of ICAM-1 modulation in the monocyte/macrophage system, which in turn could have a strong impact on the interaction with T lymphocytes and cell migration. Thus, ICAM-1 can be considered as a rapid-reacting and sustained gravity-regulated molecule in mammalian cells. PMID:25654110

Paulsen, Katrin; Tauber, Svantje; Dumrese, Claudia; Bradacs, Gesine; Simmet, Dana M.; Gölz, Nadine; Hauschild, Swantje; Raig, Christiane; Engeli, Stephanie; Gutewort, Annett; Hürlimann, Eva; Biskup, Josefine; Rieder, Gabriela; Hofmänner, Daniel; Mutschler, Lisa; Krammer, Sonja; Philpot, Claudia; Huge, Andreas; Lier, Hartwin; Barz, Ines; Engelmann, Frank; Layer, Liliana E.; Thiel, Cora S.

2015-01-01

130

Polybacterial challenge enhances HIV reactivation in latently infected macrophages and dendritic cells  

PubMed Central

A polymicrobial infection comprising subgingival biofilms is the trigger for the chronic immunoinflammatory lesions of periodontitis. These microbial biofilms interface with host immune cells that increase with progressing disease and could result in HIV reactivation in HIV-1-infected patients. Previous reports have focused on the ability of monospecies challenge of macrophages and dendritic cells to detail molecular aspects of their detection and signalling pathways. This study provides a seminal description of the responses of macrophages and dendritic cells to a polybacterial challenge using various oral bacteria as prototype stimuli to examine these response characteristics. The investigation employed a model of HIV-promoter activation and reactivation of HIV viral replication. Oral Gram-negative bacteria elicited significantly greater levels of HIV promoter activation and viral replication from all cell types, compared with Gram-positive bacteria. Selected combinations of oral Gram-negative bacteria elicited synergistic HIV promoter activation and viral replication in macrophages and immature dendritic cells. In mature dendritic cells, there was no synergism in HIV promoter activation and viral replication. Gram-positive bacteria showed no synergism in any cell model. These findings support the importance of determining the characteristics and impact of polybacterial challenges on immune cells to clarify the potential immune recognition and antigen processing that can occur in the oral cavity. PMID:21073452

Huang, Chifu B; Alimova, Yelena V; Strange, Samantha; Ebersole, Jeffrey L

2011-01-01

131

Macrophage metalloelastase: stretching therapeutic opportunities.  

PubMed

While tissue macrophages are at the first line of microbial host defense, they are also convenient hideouts for pathogens escaping immune attack. Houghton et al. discovered that alveolar macrophage mobilizes macrophage metalloelastase to destroy bacteria present inside the cell. PMID:19679644

He, Jeannie Q; Campagne, Menno van Lookeren

2009-12-01

132

Autophagy enhances NF?B activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity.  

PubMed

Immune responses must be well restrained in a steady state to avoid excessive inflammation. However, such restraints are quickly removed to exert antimicrobial responses. Here we report a role of autophagy in an early host antifungal response by enhancing NF?B activity through A20 sequestration. Enhancement of NF?B activation is achieved by autophagic depletion of A20, an NF?B inhibitor, in F4/80(hi) macrophages in the spleen, peritoneum and kidney. We show that p62, an autophagic adaptor protein, captures A20 to sequester it in the autophagosome. This allows the macrophages to release chemokines to recruit neutrophils. Indeed, mice lacking autophagy in myeloid cells show higher susceptibility to Candida albicans infection due to impairment in neutrophil recruitment. Thus, at least in the specific aforementioned tissues, autophagy appears to break A20-dependent suppression in F4/80(hi) macrophages, which express abundant A20 and contribute to the initiation of efficient innate immune responses. PMID:25609235

Kanayama, Masashi; Inoue, Makoto; Danzaki, Keiko; Hammer, Gianna; He, You-Wen; Shinohara, Mari L

2015-01-01

133

Constant light suppresses production of Met-enkephalin-containing peptides in cultured splenic macrophages and impairs primary immune response in rats.  

PubMed

The light-dark cycle is an environmental factor that influences immune physiology, and so, variations of the photoperiod length result in altered immune responsivity. Macrophage physiology comprises a spectrum of functions that goes from host defense to immune down-regulation, in addition to their homeostatic activities. Macrophages also play a key role in the transition from innate to adaptive immune responses. Met-enkephalin (MEnk) has been recognized as a modulator of macrophage physiology acting in an autocrine or paracrine fashion to influence macrophage activation, phenotype polarization and production of cytokines that would enhance lymphocyte activation at early stages of an immune response. Previously it was shown that splenic MEnk tissue content is reduced in rats exposed to constant light. In this work, we explored whether production of Met-enkephalin-containing peptides (MECPs) in cultured splenic macrophages is affected by exposure of rats to a constant light regime. In addition, we explored whether primary immune response was impaired under this condition. We found that in rats, 15 days in constant light was sufficient to disrupt their general activity rhythm. Splenic MEnk content oscillations and levels were also blunted throughout a 24-h period in animals subjected to constant light. In agreement, de novo synthesis of MECPs evaluated through incorporation of (35)S-methionine was reduced in splenic macrophages from rats exposed to constant light. Moreover, MECPs immunocytochemistry showed a decrease in the intracellular content and lack of granule-like deposits in this condition. Furthermore, we found that primary T-dependent antibody response was compromised in rats exposed to constant light. In those animals, pharmacologic treatment with MEnk increased IFN-?-secreting cells. Also, IL-2 secretion from antigen-stimulated splenocytes was reduced after incubation with naloxone, suggesting that immune-derived opioid peptides and stimulation of opioid receptors are involved in this process. Thus, the immune impairment observed from early stages of the response in constant light-subjected rats, could be associated with reduced production of macrophage-derived enkephalins, leading to a sub-optimal interaction between macrophages and lymphocytes in the spleen and the subsequent deficiency in antibody production. PMID:25245012

Valdés-Tovar, Marcela; Escobar, Carolina; Solís-Chagoyán, Héctor; Asai, Miguel; Benítez-King, Gloria

2014-09-23

134

Bone marrow: all the cells of the immune system are derived from stem cells in the bone marrow. The bone  

E-print Network

Bone marrow: all the cells of the immune system are derived from stem cells in the bone marrow. The bone marrow is the site of origin of red blood cells, white cells (including lymphocytes and macrophages) and platelets. Thymus: in the thymus gland lymphoid cells undergo a process of maturation

Morante, Silvia

135

The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter  

SciTech Connect

Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 {mu}m or less, PM{sub 10}) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 {mu}m or less, PM{sub 2.5}) and ultrafine particles (0.1 {mu}m or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-{kappa}B and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1{beta}, IL-6, and tumor necrosis factor-{alpha}] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-{kappa}B pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

Miyata, Ryohei; Eeden, Stephan F. van, E-mail: Stephan.vanEeden@hli.ubc.ca

2011-12-15

136

Cell-mimetic coatings for immune spheres.  

PubMed

Extrinsically induced or engineered cells are providing new therapeutic means in emerging fields such as cell therapeutics, immunomodulation and regenerative medicine. We are demonstrating a spatial induction method using lipid coatings, which can change signal presentation strength from material surface to adherent macrophage cells, that induce early cell-cell interaction leading to organotypic morphology. For that, we have developed a cell mimetic lipid coating with a rafts size to the order of transmembrane proteins (<10 nm) with enhanced lateral elastic properties. Such surface coatings are capable of reducing adherent macrophage spreading, while enabling early induction of cell-cell interaction to form organotypic macrophage colonies or "spheres" (M-spheres). PMID:25454756

Kaladhar, K; Renz, H; Sharma, C P

2014-11-01

137

Korean mistletoe lectin (KML-IIU) and its subchains induce nitric oxide (NO) production in murine macrophage cells  

Microsoft Academic Search

Synthesis of nitric oxide (NO) is one of the important effector functions of innate immune cells. Although several reports\\u000a have indicated mistletoe lectins induce immune cells to produce cytokines, studies regarding the activities of the lectins\\u000a in the production of NO have been very limited. Here, we report on the induction of NO synthesis in a murine macrophage cell\\u000a line,

Tae Bong Kang; Yung Choon Yoo; Kwan Hee Lee; Ho Sup Yoon; Erk Her; Seong Kyu Song

2008-01-01

138

Responses of macrophages to the danger signals released from necrotic cells.  

PubMed

The immune system maintains homeostasis by recognizing and responding to cell death caused by various stresses. The immune response is considered to be elicited by 'danger signals' released from necrotic cells. However, the identity of the danger signals remains elusive. In this study, we focused on the expression of chemokines by macrophages stimulated with necrotic cells. In mouse bone-marrow-derived macrophages, the chemokine monocyte chemoattractant protein (MCP)-3 was induced at both the mRNA and protein levels in response to heat-killed murine cells. The induction of MCP-3 was also observed in MyD88-deficient macrophages, indicating that Toll-like receptors and the IL-1 receptor are not involved in this response. Consistent with this observation, the activation of NF-?B was not detected in RAW264.7 macrophages stimulated with necrotic cells. Treatments with proteinase K, DNaseI or RNaseA did not affect the ' STIMULATING ACTIVITY': of necrotic cells. In contrast, treatment with apyrase, which removes phosphates from nucleoside tri- and di-phosphates, abolished the inducing activity. Purified UDP at 30 µM concentration elicited similar induction of MCP-3 in RAW264.7 macrophages. Small interfering RNA-mediated knock-down of the UDP receptor P2Y6 in RAW264.7 cells significantly reduced the induction of MCP-3 in response to necrotic cells, but not its induction by lipopolysaccharide. Furthermore, ectopic expression of the P2Y6 receptor in HEK293 cells conferred responsiveness to necrotic cells. These results suggest that UDP released by necrotic cells plays a critical role as an endogenous danger signal and that P2Y6 is required for the induction of MCP-3 in response to necrotic cells. PMID:25096411

Kimura, Toshifumi; Kobayashi, Shuhei; Hanihara-Tatsuzawa, Fumito; Sayama, Aoi; MaruYama, Takashi; Muta, Tatsushi

2014-12-01

139

Impact of alginate-producing Pseudomonas aeruginosa on alveolar macrophage apoptotic cell clearance.  

PubMed

Pseudomonas aeruginosa infection is a hallmark of lung disease in cystic fibrosis. Acute infection with P. aeruginosa profoundly inhibits alveolar macrophage clearance of apoptotic cells (efferocytosis) via direct effect of virulence factors. During chronic infection, P. aeruginosa evades host defense by decreased virulence, which includes the production or, in the case of mucoidy, overproduction of alginate. The impact of alginate on innate immunity, in particular on macrophage clearance of apoptotic cells is not known. We hypothesized that P. aeruginosa strains that exhibit reduced virulence impair macrophage clearance of apoptotic cells and we investigated if the polysaccharide alginate produced by mucoid P. aeruginosa is sufficient to inhibit alveolar macrophage efferocytosis. Rat alveolar or human peripheral blood monocyte (THP-1)-derived macrophage cell lines were exposed in vitro to exogenous alginate or to wild type or alginate-overproducing mucoid P. aeruginosa prior to challenge with apoptotic human Jurkat T-lymphocytes. The importance of LPS contamination and that of structural integrity of alginate polymers was tested using alginate of different purities and alginate lyase, respectively. Alginate inhibited alveolar macrophage efferocytosis in a dose- and time-dependent manner. This effect was augmented but not exclusively attributed to lipopolysaccharide (LPS) present in alginates. Alginate-producing P. aeruginosa inhibited macrophage efferocytosis by more than 50%. A mannuronic-specific alginate lyase did not restore efferocytosis inhibited by exogenous guluronic-rich marine alginate, but had a marked beneficial effect on efferocytosis of alveolar macrophages exposed to mucoid P. aeruginosa. Despite decreased virulence, mucoid P. aeruginosa may contribute to chronic airway inflammation through significant inhibition of alveolar clearance of apoptotic cells and debris. The mechanism by which mucoid bacteria inhibit efferocytosis may involve alginate production and synergy with LPS, suggesting that alginate lyase may be an attractive therapeutic approach to airway inflammation in cystic fibrosis and other chronic obstructive pulmonary diseases characterized by P. aeruginosa colonization. PMID:25027418

McCaslin, Charles A; Petrusca, Daniela N; Poirier, Christophe; Serban, Karina A; Anderson, Gregory G; Petrache, Irina

2015-01-01

140

Adipocytes as immune regulatory cells  

PubMed Central

Obesity is a chronic inflammatory state and adipocytes are capable of contributing to this inflammation by their production of inflammatory mediators. The present study used fibroblast-derived adipocytes and normal spleen cells as a model to determine if adipocytes can also serve as immune regulatory cells by modulating the functions of conventional immune cells. Media conditioned by the adipocytes stimulated release of the Th1-type cytokines IL-2, IFN-? and GM-CSF from cultures of normal spleen cells. The adipocytes also stimulated spleen cell release of inhibitory cytokines, although to varying degrees. This included IL-10, IL-13 and, to a lesser extent, IL-4. Spleen cell production of the inflammatory cytokines IL-6, TNF-? and IL-9 was stimulated by adipocytes, although production of the Th17-derived cytokine, IL-17, was not stimulated. The adipocyte-conditioned medium did not stimulate production of predominantly monocytes-derived chemokines CXCL9, CCL2, CCL3, CCL4, but stimulated production of the predominantly T-cell-derived chemokine CCL5. In all cases where cytokine/chemokine production from spleen cells was stimulated by adipocytes, it was to a far greater level than was produced by the adipocytes themselves. Studies initiated to determine the identity of the adipocyte-derived mediators showed that the spleen cell modulation could not be attributed to solely adiponectin or leptin. Studies to determine the source of some of the cytokines whose production was stimulated by adipocytes showed that expression of the inflammatory cytokine IL-6 was not increased in either CD4+ or CD8+ T-cell. When the splenic T-cells were examined for IFN-?, the adipocyte stimulation of IFN-? was within CD8+ T-cells, not CD4+ T-cells. These studies show that adipocytes may be able to serve as immune regulatory cells to stimulate conventional immune cells to release a spectrum of immune mediators. PMID:23587489

Vielma, Silvana A.; Klein, Richard L.; Levingston, Corinne A.; Young, M. Rita I.

2013-01-01

141

Toll-like receptor 9 regulates the lung macrophage phenotype and host immunity in murine pneumonia caused by Legionella pneumophila.  

PubMed

Experiments were performed to determine the contribution of TLR9 to the generation of protective immunity against the intracellular respiratory bacterial pathogen Legionella pneumophila. In initial studies, we found that the intratracheal (i.t.) administration of L. pneumophila to mice deficient in TLR9 (TLR9(-/-)) resulted in significantly increased mortality, which was associated with an approximately 10-fold increase in the number of lung CFU compared to that of wild-type BALB/c mice. Intrapulmonary bacterial challenge in TLR9(-/-) mice resulted in the reduced accumulation of myeloid dendritic cells (DC) and activated CD4(+) T cells. Lung macrophages isolated from Legionella-infected TLR9(-/-) mice displayed the impaired internalization of bacteria and evidence of alternative rather than classical activation, as manifested by the markedly reduced expression of nitric oxide and type 1 cytokines, whereas the expression of Fizz-1 and arginase-1 was enhanced. The adoptive transfer of bone marrow-derived DC from syngeneic wild-type, but not TLR9(-/-), mice administered i.t. reconstituted anti-legionella immunity and restored the macrophage phenotype in TLR9(-/-) mice. Finally, the i.t., but not intraperitoneal, administration of the TLR9 agonist molecule CpG oligodeoxynucleotide stimulated protective immunity in Legionella-infected mice. In total, our findings indicate that TLR9 is required for effective innate immune responses against the intracellular bacterial pathogen L. pneumophila, and approaches to maximize TLR9-mediated responses may serve as a means to augment antibacterial immunity in pneumonia. PMID:18426877

Bhan, Urvashi; Trujillo, Glenda; Lyn-Kew, Kenneth; Newstead, Michael W; Zeng, Xianying; Hogaboam, Cory M; Krieg, Arthur M; Standiford, Theodore J

2008-07-01

142

Peritoneal catheter implantation elicits IL-10-producing immune-suppressor macrophages through a MyD88-dependent pathway.  

PubMed

Catheters are implanted into the peritoneal cavity during the process of peritoneal dialysis. Though these catheters may be effective and beneficial, the impact of catheters on the immune system is poorly understood. Catheters and other devices implanted in the peritoneal cavity elicit a foreign body reaction. However, the immunological consequences of this remain uncharacterized. To model this, catheters were implanted into the peritoneal cavity of healthy mice. Catheter implantation induced rapid cellular changes within the peritoneal cavity. Whereas B-cells and T-cells were reduced, catheter implantation was associated with the rapid expansion of F4/80-low-positive, CD11b-positive macrophages that elaborated IL-10, and suppressed T-cell division and Th1 skewing in co-culture assays. Peritoneal catheter elicited macrophages had increased Jmjd3 but reduced NF-?B activation, and their emergence was MyD88-dependent. Collectively, these studies indicate that foreign body implantation into the peritoneal cavity is associated with the expansion of suppressor macrophages. Whether peritoneal cavity catheter implantation may have systemic immunoregulatory roles remains to be explored. PMID:22341910

Min, So-Youn; Fu, Yuyang; Hutcheson, Jack; Wu, Tianfu; Khobahy, Elhaum; Zhu, Jiankun; Vanarsa, Kamala; Du, Yong; Park, Min-Jung; Park, Hyun-Sil; Saxena, Ramesh; Kim, Ho-Youn; Mohan, Chandra

2012-04-01

143

Disruption of SIRP? signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts  

PubMed Central

Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRP?-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRP? variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRP? signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRP?-Fc fusion protein to disrupt SIRP?–CD47 engagement. Treatment with SIRP?-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRP?-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRP? signaling to enhance macrophage-mediated elimination of AML. PMID:22945919

Theocharides, Alexandre P.A.; Jin, Liqing; Cheng, Po-Yan; Prasolava, Tatiana K.; Malko, Andrei V.; Ho, Jenny M.; Poeppl, Armando G.; van Rooijen, Nico; Minden, Mark D.; Danska, Jayne S.; Dick, John E.

2012-01-01

144

Disruption of SIRP? signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts.  

PubMed

Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRP?-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRP? variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRP? signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRP?-Fc fusion protein to disrupt SIRP?-CD47 engagement. Treatment with SIRP?-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRP?-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRP? signaling to enhance macrophage-mediated elimination of AML. PMID:22945919

Theocharides, Alexandre P A; Jin, Liqing; Cheng, Po-Yan; Prasolava, Tatiana K; Malko, Andrei V; Ho, Jenny M; Poeppl, Armando G; van Rooijen, Nico; Minden, Mark D; Danska, Jayne S; Dick, John E; Wang, Jean C Y

2012-09-24

145

Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity  

NASA Astrophysics Data System (ADS)

The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca2+ waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca2+-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.

Westphalen, Kristin; Gusarova, Galina A.; Islam, Mohammad N.; Subramanian, Manikandan; Cohen, Taylor S.; Prince, Alice S.; Bhattacharya, Jahar

2014-02-01

146

Epithelial cells modulate genes associated with NF kappa B activation in co-cultured human macrophages.  

PubMed

Macrophages located in airways and the alveolar space are continually exposed to different signals from the respiratory mucosa. In this respect, epithelial cells represent an important source of cytokines and mediators modulating the state of activation and/or differentiation of mononuclear phagocytes. Many of the proinflammatory genes induced in macrophages during immune and immunopathological reactions are regulated by transcription factor NF kappa B. The aim of our study was to characterize changes in the expression of genes associated with NF kappa B activation and signalling in THP-1 human macrophages co-cultured with A549 respiratory epithelial cells. At least 4-fold upregulation of mRNA level was found in 29 of 84 tested genes including genes for multiple cytokines and chemokines, membrane antigens and receptors, and molecules associated with NF kappa B signalling. The mRNA induction was confirmed at the level of protein expression by evaluating the release of IL-6 and IL-8 and by ICAM-1 expression. Blocking of one NF?B subunit by p65 siRNA inhibited the production of IL-6 in both cell types while IL-8 release from THP-1 cells did not seem to be affected. We conclude from our data that unstimulated respiratory epithelial cells regulate genes associated with NF kappa B dependent immune responses in human macrophages and that these interactions may play a key role in immediate responses in the respiratory mucosa. PMID:21601940

Striz, I; Brabcova, E; Kolesar, L; Liu, X D; Brabcova, I; Sekerkova, A; Poole, J A; Jaresova, M; Slavcev, A; Rennard, S I

2011-10-01

147

Play the Immune System Defender Game  

MedlinePLUS

... Questionnaire The Immune System Play the Immune System Game About the game Granulocytes, macrophages and dendritic cells are immune cells ... last will in Paris. Play the Blood Typing Game Try to save some patients and learn about ...

148

Norcantharidin facilitates LPS-mediated immune responses by up-regulation of AKT/NF-?B signaling in macrophages.  

PubMed

Norcantharidin (NCTD), a demethylated analog of cantharidin, is a common used clinical drug to inhibit proliferation and metastasis of cancer cells. But the role of NCTD in modulating immune responses remains unknown. Here, we investigated the function and mechanism of NCTD in regulation of TLR4 associated immune response in macrophages. We evaluated the influence of NCTD on host defense against invaded pathogens by acute peritonitis mouse model, ELISA, Q-PCR, nitrite quantification, phagocytosis assay and gelatin zymography assay. Our data showed that the survival and the serum concentrations of IL-6 and TNF-? were all enhanced by NCTD significantly in peritonitis mouse model. Accordingly, LPS-induced cytokine, nitric oxide and MMP-9 production as well as the phagocytosis of bacteria were all up-regulated by NCTD in a dose dependent manner in both RAW264.7 cells and bone marrow-derived macrophages (BMMs). Then we further analyzed TLR4 associated signaling pathway by Western blot, Immunofluorescence and EMSA in the presence or absence of LPS. The phosphorylation of AKT and p65 at serine 536 but not serine 468 was enhanced obviously by NCTD in a dose dependent manner, whereas the degradation of I?B? was little effected. Consequently, the nuclear translocation and DNA binding ability of NF-?B was also increased by NCTD obviously in RAW264.7 cells. Our results demonstrated that NCTD could facilitate LPS-mediated immune response through promoting the phosphorylation of AKT/p65 and transcriptional activity of NF-?B, thus reprofiling the traditional anti-tumor drug NCTD as a novel immune regulator in promoting host defense against bacterial infection. PMID:22984593

Zhao, Qufei; Qian, Yu; Li, Ruimei; Tan, Binghe; Han, Honghui; Liu, Mingyao; Qian, Min; Du, Bing

2012-01-01

149

Norcantharidin Facilitates LPS-Mediated Immune Responses by Up-Regulation of AKT/NF-?B Signaling in Macrophages  

PubMed Central

Norcantharidin (NCTD), a demethylated analog of cantharidin, is a common used clinical drug to inhibit proliferation and metastasis of cancer cells. But the role of NCTD in modulating immune responses remains unknown. Here, we investigated the function and mechanism of NCTD in regulation of TLR4 associated immune response in macrophages. We evaluated the influence of NCTD on host defense against invaded pathogens by acute peritonitis mouse model, ELISA, Q-PCR, nitrite quantification, phagocytosis assay and gelatin zymography assay. Our data showed that the survival and the serum concentrations of IL-6 and TNF-? were all enhanced by NCTD significantly in peritonitis mouse model. Accordingly, LPS-induced cytokine, nitric oxide and MMP-9 production as well as the phagocytosis of bacteria were all up-regulated by NCTD in a dose dependent manner in both RAW264.7 cells and bone marrow-derived macrophages (BMMs). Then we further analyzed TLR4 associated signaling pathway by Western blot, Immunofluorescence and EMSA in the presence or absence of LPS. The phosphorylation of AKT and p65 at serine 536 but not serine 468 was enhanced obviously by NCTD in a dose dependent manner, whereas the degradation of I?B? was little effected. Consequently, the nuclear translocation and DNA binding ability of NF-?B was also increased by NCTD obviously in RAW264.7 cells. Our results demonstrated that NCTD could facilitate LPS-mediated immune response through promoting the phosphorylation of AKT/p65 and transcriptional activity of NF-?B, thus reprofiling the traditional anti-tumor drug NCTD as a novel immune regulator in promoting host defense against bacterial infection. PMID:22984593

Li, Ruimei; Tan, Binghe; Han, Honghui; Liu, Mingyao; Qian, Min; Du, Bing

2012-01-01

150

Human Dermal CD14+ Cells Are a Transient Population of Monocyte-Derived Macrophages  

PubMed Central

Summary Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141hiXCR1+CLEC9A+ DCs and CD1c+ DCs are murine CD103+ DCs and CD64?CD11b+ DCs. In addition, human tissues also contain CD14+ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14+ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14+ monocytes and dermal CD14+ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14+ cells are CD11b+CD64+ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system. PMID:25200712

McGovern, Naomi; Schlitzer, Andreas; Gunawan, Merry; Jardine, Laura; Shin, Amanda; Poyner, Elizabeth; Green, Kile; Dickinson, Rachel; Wang, Xiao-nong; Low, Donovan; Best, Katie; Covins, Samuel; Milne, Paul; Pagan, Sarah; Aljefri, Khadija; Windebank, Martin; Saavedra, Diego Miranda; Larbi, Anis; Wasan, Pavandip Singh; Duan, Kaibo; Poidinger, Michael; Bigley, Venetia; Ginhoux, Florent; Collin, Matthew; Haniffa, Muzlifah

2014-01-01

151

Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung  

PubMed Central

Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces, such as the lung. To overcome this, we generated human IL-3/GM-CSF knock-in (hIL-3/GM-CSF KI) mice. These mice faithfully expressed human GM-CSF and IL-3 and developed pulmonary alveolar proteinosis because of elimination of mouse GM-CSF. We demonstrate that hIL-3/GM-CSF KI mice engrafted with human CD34+ hematopoietic cells had improved human myeloid cell reconstitution in the lung. In particular, hIL-3/GM-CSF KI mice supported the development of human alveolar macrophages that partially rescued the pulmonary alveolar proteinosis syndrome. Moreover, human alveolar macrophages mounted correlates of a human innate immune response against influenza virus. The hIL-3/GM-CSF KI mice represent a unique mouse model that permits the study of human mucosal immune responses to lung pathogens. PMID:21262803

Willinger, Tim; Rongvaux, Anthony; Takizawa, Hitoshi; Yancopoulos, George D.; Valenzuela, David M.; Murphy, Andrew J.; Auerbach, Wojtek; Eynon, Elizabeth E.; Stevens, Sean; Manz, Markus G.; Flavell, Richard A.

2011-01-01

152

Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice.  

PubMed

In type 1 diabetes (T1D), reactive oxygen species (ROS) and proinflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic ? cells while promoting autoreactive T cell maturation. Superoxide-deficient nonobese diabetic mice (NOD.Ncf1(m1J)) are resistant to spontaneous diabetes, revealing the integral role of ROS signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-M?) from NOD and NOD.Ncf1(m1J) mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-?B signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1(m1J) BM-M? exhibited a 2- and 10-fold decrease in TNF-? and IFN-? proinflammatory cytokine synthesis, respectively, in contrast to NOD BM-M?. Optimal expression of IFN-?/? is not solely dependent on superoxide synthesis, but requires p47(phox) to function in a NOX-independent manner to mediate type I interferon synthesis. Interestingly, MHC-II I-A(g7) expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-A(g7) downregulation. These findings suggest that defective innate immune-pattern-recognition receptor activation and subsequent decrease in TNF-? and IFN-? proinflammatory cytokine synthesis necessary for autoreactive T cell maturation may contribute to the T1D protection observed in NOD.Ncf1(m1J) mice. PMID:22361747

Seleme, Maria C; Lei, Weiqi; Burg, Ashley R; Goh, Kah Yong; Metz, Allison; Steele, Chad; Tse, Hubert M

2012-05-01

153

Dysregulated TLR3-Dependent Signaling and Innate Immune Activation in Superoxide-Deficient Macrophages From Non-Obese Diabetic Mice  

PubMed Central

In Type 1 diabetes (T1D), reactive oxygen species (ROS) and pro-inflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic ?-cells while promoting autoreactive T cell maturation. Superoxide-deficient Non-Obese Diabetic mice (NOD.Ncf1m1J) are resistant to spontaneous diabetes, revealing the integral role of ROS-signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-M?) from NOD and NOD.Ncf1m1J mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-?B signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1m1J BM-M? exhibited a 2- and 10-fold decrease in TNF-? and IFN-? pro-inflammatory cytokine synthesis, respectively, in contrast to NOD BM-M?. Optimal expression of IFN-?/? is not solely dependent on superoxide synthesis, but requires p47phox to function in a NOX-independent manner to mediate Type I interferon synthesis. Interestingly, MHC-II I-Ag7 expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-Ag7 down-regulation. These findings suggest that defective innate immune pattern-recognition receptor activation and subsequent decrease in TNF-? and IFN-? pro-inflammatory cytokine synthesis necessary for autoreactive T cell maturation, may contribute to the T1D protection observed in NOD.Ncf1m1J mice. PMID:22361747

Seleme, Maria C.; Lei, Weiqi; Burg, Ashley R.; Goh, Kah Yong; Metz, Allison; Steele, Chad; Tse, Hubert M.

2013-01-01

154

Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells  

Microsoft Academic Search

The action of Ginkgo biloba extract (GBE) as an antioxidant was studied using various models of oxidative stress in macrophages and vascular endothelial cells. GBE was incubated with murine macrophages (J774) at 37°C and 5% CO2 for 1 h; oxidative burst was triggered by zymosan. The intensity of fluorescence was measured directly in 96-well plates using a computerized microplate fluorometer

Yongqi Rong; Zhaohui Geng; Benjamin H. S. Lau

1996-01-01

155

Engagement of the Mannose Receptor by Tumoral Mucins Activates an Immune Suppressive Phenotype in Human Tumor-Associated Macrophages  

PubMed Central

Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype. PMID:21331365

Allavena, P.; Chieppa, M.; Bianchi, G.; Solinas, G.; Fabbri, M.; Laskarin, G.; Mantovani, A.

2010-01-01

156

Integrative Model of the Immune Response to a Pulmonary Macrophage Infection: What Determines the Infection Duration?  

PubMed Central

The immune mechanisms which determine the infection duration induced by pathogens targeting pulmonary macrophages are poorly known. To explore the impact of such pathogens, it is indispensable to integrate the various immune mechanisms and to take into account the variability in pathogen virulence and host susceptibility. In this context, mathematical models complement experimentation and are powerful tools to represent and explore the complex mechanisms involved in the infection and immune dynamics. We developed an original mathematical model in which we detailed the interactions between the macrophages and the pathogen, the orientation of the adaptive response and the cytokine regulations. We applied our model to the Porcine Respiratory and Reproductive Syndrome virus (PRRSv), a major concern for the swine industry. We extracted value ranges for the model parameters from modelling and experimental studies on respiratory pathogens. We identified the most influential parameters through a sensitivity analysis. We defined a parameter set, the reference scenario, resulting in a realistic and representative immune response to PRRSv infection. We then defined scenarios corresponding to graduated levels of strain virulence and host susceptibility around the reference scenario. We observed that high levels of antiviral cytokines and a dominant cellular response were associated with either short, the usual assumption, or long infection durations, depending on the immune mechanisms involved. To identify these mechanisms, we need to combine the levels of antiviral cytokines, including , and . The latter is a good indicator of the infected macrophage level, both combined provide the adaptive response orientation. Available PRRSv vaccines lack efficiency. By integrating the main interactions between the complex immune mechanisms, this modelling framework could be used to help designing more efficient vaccination strategies. PMID:25233096

Go, Natacha; Bidot, Caroline; Belloc, Catherine; Touzeau, Suzanne

2014-01-01

157

Reciprocal communication between endometrial stromal cells and macrophages.  

PubMed

This study tested the hypothesis that reciprocal communication occurs between macrophages and cultured human endometrial stromal cells and that this communication may contribute to the pathology of endometriosis. An endometrial stromal cell line (telomerase-immortalized human endometrial stromal cell [T-HESC]) was treated with macrophage-conditioned medium (CM) +/- estradiol + progesterone. Macrophages were treated without or with T-HESC CM. DNA microarray identified 716 differentially expressed genes in T-HESCs in response to factors secreted by macrophages. Upregulated genes in T-HESC included interleukin 8 (IL-8)/chemokine (C-X-C motif) ligand 8 (CXCL8), matrix metalloproteinase 3 (MMP3), phospholamban, cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), tenascin C, and nicotinamide N-methyltransferase (NNMT), whereas integrin alpha-6 was downregulated. In contrast, 15 named genes were differentially expressed in macrophages in response to factors secreted by endometrial stromal cells. The data document reciprocal communication between macrophages and endometrial stromal cells and suggest that interaction with macrophages stimulates the expression of genes in endometrial stromal cells that may support the establishment of endometriosis. PMID:20601541

Eyster, Kathleen M; Hansen, Keith A; Winterton, Emily; Klinkova, Olga; Drappeau, Donis; Mark-Kappeler, Connie J

2010-09-01

158

TGF-?1-Induced Epithelial–Mesenchymal Transition Promotes Monocyte/Macrophage Properties in Breast Cancer Cells  

PubMed Central

Breast cancer progression toward metastatic disease is linked to re-activation of epithelial–mesenchymal transition (EMT), a latent developmental process. Breast cancer cells undergoing EMT lose epithelial characteristics and gain the capacity to invade the surrounding tissue and migrate away from the primary tumor. However, less is known about the possible role of EMT in providing cancer cells with properties that allow them to traffic to distant sites. Given the fact that pro-metastatic cancer cells share a unique capacity with immune cells to traffic in-and-out of blood and lymphatic vessels we hypothesized that tumor cells undergoing EMT may acquire properties of immune cells. To study this, we performed gene-profiling analysis of mouse mammary EpRas tumor cells that had been allowed to adopt an EMT program after long-term treatment with TGF-?1 for 2?weeks. As expected, EMT cells acquired traits of mesenchymal cell differentiation and migration. However, in addition, we found another cluster of induced genes, which was specifically enriched in monocyte-derived macrophages, mast cells, and myeloid dendritic cells, but less in other types of immune cells. Further studies revealed that this monocyte/macrophage gene cluster was enriched in human breast cancer cell lines displaying an EMT or a Basal B profile, and in human breast tumors with EMT and undifferentiated (ER?/PR?) characteristics. The results identify an EMT-induced monocyte/macrophage gene cluster, which may play a role in breast cancer cell dissemination and metastasis. PMID:25674539

Johansson, Joel; Tabor, Vedrana; Wikell, Anna; Jalkanen, Sirpa; Fuxe, Jonas

2015-01-01

159

Cell mechanics of alveolar epithelial cells (AECs) and macrophages (AMs).  

PubMed

Cell mechanics provides an integrated view of many biological phenomena which are intimately related to cell structure and function. Because breathing constitutes a sustained motion synonymous with life, pulmonary cells are normally designed to support permanent cyclic stretch without breaking, while receiving mechanical cues from their environment. The authors study the mechanical responses of alveolar cells, namely epithelial cells and macrophages, exposed to well-controlled mechanical stress in order to understand pulmonary cell response and function. They discuss the principle, advantages and limits of a cytoskeleton-specific micromanipulation technique, magnetic bead twisting cytometry, potentially applicable in vivo. They also compare the pertinence of various models (e.g., rheological; power law) used to extract cell mechanical properties and discuss cell stress/strain hardening properties and cell dynamic response in relation to the structural tensegrity model. Overall, alveolar cells provide a pertinent model to study the biological processes governing cellular response to controlled stress or strain. PMID:18565804

Féréol, Sophie; Fodil, Redouane; Pelle, Gabriel; Louis, Bruno; Isabey, Daniel

2008-11-30

160

CD14 influences host immune responses and alternative activation of macrophages during Schistosoma mansoni infection.  

PubMed

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14(-/-) mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14(-/-) mice exhibited increased production of CD4(+)-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4(+)Foxp3(+)IL-10(+) regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14(-/-) mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14(-/-) phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14(-/-) mice and normalized the M2 and CD4(+) Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14(-/-) mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4R?-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4(+) T cell biasing during helminth infection. PMID:24866794

Tundup, Smanla; Srivastava, Leena; Nagy, Tamas; Harn, Donald

2014-08-01

161

Evolution of B Cell Immunity  

PubMed Central

Two types of adaptive immune strategies are known to have evolved in vertebrates: the VLR-based system, which is present in jawless organisms and is mediated by VLRA and VLRB lymphocytes, and the BCR/TCR-based system, which is present in jawed species and is provided by B and T cell receptors expressed on B and T cells, respectively. Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates. We point out the critical role of nonclassical species and comparative immunology studies in the understanding of B cell immunity. Because nonclassical models include species relevant to veterinary medicine, basic science research performed in these animals contributes to the knowledge required for the development of more efficacious vaccines against emerging pathogens. PMID:25340015

Sunyer, J. Oriol

2013-01-01

162

Phospholipase C-? in Immune Cells  

PubMed Central

Great progress has recently been made in structural and functional research of phospholipase C (PLC)-?. We now understand how PLC-? isoforms (?1-?4) are activated by GTP-bound G?q downstream of G protein-coupled receptors. Numerous studies indicate that PLC-?s participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-?3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein-tyrosine phosphatase SHP-1, with which PLC-?3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. PMID:23981313

Kawakami, Toshiaki; Xiao, Wenbin

2013-01-01

163

Polybacterial challenge effects on cytokine/chemokine production by macrophages and dendritic cells  

PubMed Central

Objective To investigate the polymicrobial infection of periodontal disease, which elicits inflammatory mediators/cytokines/chemokines in the local gingival tissues, and a polybacterial challenge of antigen-presenting cells, e.g. macrophages and dendritic cells (DCs), at the mucosal surface. Materials and methods The cytokine/chemokine profiles of human macrophages and DCs in response to polybacterial challenges were investigated. Results Oral Gram-negative bacteria elicited significantly greater IL-8 levels from macrophages, compared to Gram-positive bacteria. Gram-positive bacteria did not show synergism in inducing this chemokine from macrophages. In contrast, pairs of oral Gram-negative bacteria elicited synergistic production of IL-8 by macrophages. Similar results were not observed with TNF?, which only appeared additive with the polybacterial challenge. Selected Gram-negative bacterial pairs synergized in IL-6 production by immature DCs. In mature DCs (mDCs), a Porphyromonas gingivalis/Fusobacterium nucleatum and Porphyromonas intermedia/F. nucleatum polybacterial challenge resulted in significant synergism for IL-6 and TNF? levels. However, only the Pi/Fn combination synergized for IL-12 production and there appeared to be no polybacterial effect on IL-10 production by the mDCs. Conclusions These results indicate that a polybacterial challenge of cells linking innate and adaptive immune responses results in varied response profiles that are dependent upon the characteristics of the microorganisms that are components of the polybacterial complex. PMID:20798974

Huang, C. B.; Altimova, Y.; Strange, S.

2013-01-01

164

Macrophages – Key Cells in the Response to Wear Debris from Joint Replacements  

PubMed Central

The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of pro-inflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented. PMID:23568608

Nich, Christophe; Takakubo, Yuya; Pajarinen, Jukka; Ainola, Mari; Salem, Abdelhakim; Sillat, Tarvo; Rao, Allison J.; Raska, Milan; Tamaki, Yasunobu; Takagi, Michiaki; Konttinen, Yrjö T.; Goodman, Stuart B.; Gallo, Jiri

2013-01-01

165

Stimulatory Effects of Polysaccharide Fraction from Solanum nigrum on RAW 264.7 Murine Macrophage Cells  

PubMed Central

The polysaccharide fraction from Solanum nigrum Linne has been shown to have antitumor activity by enhancing the CD4+/CD8+ ratio of the T-lymphocyte subpopulation. In this study, we analyzed a polysaccharide extract of S. nigrum to determine its modulating effects on RAW 264.7 murine macrophage cells since macrophages play a key role in inducing both innate and adaptive immune responses. Crude polysaccharide was extracted from the stem of S. nigrum and subjected to ion-exchange chromatography to partially purify the extract. Five polysaccharide fractions were then subjected to a cytotoxicity assay and a nitric oxide production assay. To further analyze the ability of the fractionated polysaccharide extract to activate macrophages, the phagocytosis activity and cytokine production were also measured. The polysaccharide fractions were not cytotoxic, but all of the fractions induced nitric oxide in RAW 264.7 cells. Of the five fractions tested, SN-ppF3 was the least toxic and also induced the greatest amount of nitric oxide, which was comparable to the inducible nitric oxide synthase expression detected in the cell lysate. This fraction also significantly induced phagocytosis activity and stimulated the production of tumor necrosis factor-? and interleukin-6. Our study showed that fraction SN-ppF3 could classically activate macrophages. Macrophage induction may be the manner in which polysaccharides from S. nigrum are able to prevent tumor growth. PMID:25299340

Razali, Faizan Naeem; Ismail, Amirah; Abidin, Nurhayati Zainal; Shuib, Adawiyah Suriza

2014-01-01

166

Macrophages-Key cells in the response to wear debris from joint replacements.  

PubMed

The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening, and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of proinflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented. PMID:23568608

Nich, Christophe; Takakubo, Yuya; Pajarinen, Jukka; Ainola, Mari; Salem, Abdelhakim; Sillat, Tarvo; Rao, Allison J; Raska, Milan; Tamaki, Yasunobu; Takagi, Michiaki; Konttinen, Yrjö T; Goodman, Stuart B; Gallo, Jiri

2013-10-01

167

Stimulatory effects of polysaccharide fraction from Solanum nigrum on RAW 264.7 murine macrophage cells.  

PubMed

The polysaccharide fraction from Solanum nigrum Linne has been shown to have antitumor activity by enhancing the CD4+/CD8+ ratio of the T-lymphocyte subpopulation. In this study, we analyzed a polysaccharide extract of S. nigrum to determine its modulating effects on RAW 264.7 murine macrophage cells since macrophages play a key role in inducing both innate and adaptive immune responses. Crude polysaccharide was extracted from the stem of S. nigrum and subjected to ion-exchange chromatography to partially purify the extract. Five polysaccharide fractions were then subjected to a cytotoxicity assay and a nitric oxide production assay. To further analyze the ability of the fractionated polysaccharide extract to activate macrophages, the phagocytosis activity and cytokine production were also measured. The polysaccharide fractions were not cytotoxic, but all of the fractions induced nitric oxide in RAW 264.7 cells. Of the five fractions tested, SN-ppF3 was the least toxic and also induced the greatest amount of nitric oxide, which was comparable to the inducible nitric oxide synthase expression detected in the cell lysate. This fraction also significantly induced phagocytosis activity and stimulated the production of tumor necrosis factor-? and interleukin-6. Our study showed that fraction SN-ppF3 could classically activate macrophages. Macrophage induction may be the manner in which polysaccharides from S. nigrum are able to prevent tumor growth. PMID:25299340

Razali, Faizan Naeem; Ismail, Amirah; Abidin, Nurhayati Zainal; Shuib, Adawiyah Suriza

2014-01-01

168

Proximal tubule cells stimulated by lipopolysaccharideinhibit macrophage activation  

Microsoft Academic Search

Proximal tubule cells stimulated by lipopolysaccharide inhibit macrophage activation.BackgroundTubule cells can produce a variety of cytokines, extracellular matrix (ECM) components, and adhesion molecules in vitro and in vivo. It is generally assumed that stimulated tubule cells are proinflammatory and at least partially responsible for interstitial inflammation. However, the overall effect of tubular cells on interstitial cells is unknown. In this

YIPING WANG; YUET-CHING TAY; DAVID C H HARRIS

2004-01-01

169

Dexamethasone increases ROS production and T cell suppressive capacity by anti-inflammatory macrophages.  

PubMed

Macrophages have been demonstrated to suppress T cell responses by producing reactive oxygen species (ROS) leading to the subsequent induction of T regulatory cells in a ROS-dependent manner. Macrophages may therefore be instrumental in downregulating T cell responses in situations of exacerbated immune responses. Here we investigated the effect of immunosuppressive drugs on ROS production by macrophage subsets and the subsequent effects on T cell activation. Macrophage types 1 and 2 were differentiated with GM-CSF or M-CSF, in presence or absence of dexamethasone, cyclosporine A, FK506, rapamycin, or mycophenolic acid. The ROS producing capacity of fully differentiated Mph was highest in anti-inflammatory Mph2 and not affected by exposure to immunosuppressive drugs. However, presence of rapamycin during Mph2 differentiation decreased the ROS production of these cells. In contrast, other immunosuppressive drugs, with dexamethasone being the most potent, increased the ROS producing capacity of Mph2. Intriguingly although the ROS producing ability of Mph1 was unaffected, dexamethasone strongly increased the ROS producing capabilities of dendritic cells. Both at the mRNA and protein level we found that dexamethasone enhanced the expression of NOX2 protein p47(phox). Functionally, dexamethasone further enhanced the capacity of Mph2 to suppress T cell mediated IFN-? and IL-4 production. In vivo, only in rats with normal ROS production (congenic DA.Ncf1(E3/E3)) it was observed that dexamethasone injection resulted in long-lasting upregulation of ROS production by macrophages and induced higher levels of Treg in a ROS-dependent manner. In conclusion, we show that the anti-inflammatory drug dexamethasone increases the ROS producing capacity of macrophages. PMID:22047959

Kraaij, Marina D; van der Kooij, Sandra W; Reinders, Marlies E J; Koekkoek, Karin; Rabelink, Ton J; van Kooten, Cees; Gelderman, Kyra A

2011-12-01

170

Adiponectin Induces Pro-inflammatory Programs in Human Macrophages and CD4+ T Cells  

PubMed Central

Abundant experimental and clinical data support a modulatory role for adiponectin in inflammation, dysmetabolism, and disease. Because the activation of cells involved in innate and adaptive immunity contributes to the pathogenesis of diseases such as atherosclerosis and obesity, this study investigated the role of adiponectin in human macrophage polarization and T cell differentiation. Examination of the adiponectin-induced transcriptome in primary human macrophages revealed that adiponectin promotes neither classical (M1) nor alternative (M2) macrophage activation but elicits a pro-inflammatory response that resembles M1 more closely than M2. Addition of adiponectin to polyclonally activated CD4+ T lymphocytes did not affect cell proliferation but induced mRNA expression and protein secretion of interferon (IFN)-? and interleukin (IL)-6. Adiponectin treatment of CD4+ T cells increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and signal transducer and activation of transcription (STAT) 4 and augmented T-bet expression. Inhibition of p38 with SB203580 abrogated adiponectin-induced IFN-? production, indicating that adiponectin enhances TH1 differentiation through the activation of the p38-STAT4-T-bet axis. Collectively, our results demonstrate that adiponectin can induce pro-inflammatory functions in isolated macrophages and T cells, concurring with previous observations that adiponectin induces a limited program of inflammatory activation that likely desensitizes these cells to further pro-inflammatory stimuli. PMID:22948153

Cheng, Xiang; Folco, Eduardo J.; Shimizu, Koichi; Libby, Peter

2012-01-01

171

Ginsenoside Rg1 regulates innate immune responses in macrophages through differentially modulating the NF-?B and PI3K/Akt/mTOR pathways.  

PubMed

Ginsenoside Rg1 is one of the major active components of ginseng, which has been shown to regulate the immune response of hosts. However, the mechanism underlying the immunomodulatory effect of Rg1 is incompletely understood. In this study, we aimed to explore whether and how Rg1 regulates the innate immune response in macrophages. The results showed that Rg1 treatment significantly increased tumor necrosis factor (TNF)-? but decreased interleukin-6 (IL-6) protein expression in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and mouse peritoneal macrophages. However, Rg1 reduced the mRNA levels of both cytokines in LPS-activated macrophages, which might be a consequence of decreased activation of I?B and nuclear factor-?B (NF-?B). Importantly, Rg1 treatment further promoted LPS-induced activation of the Akt/mechanistic target of rapamycin (mTOR) pathway, which is critical for controlling protein translation. The elevated Akt/mTOR signaling was likely responsible for increased production of TNF-? protein at the translational level, as suppression of this pathway by LY294002, an inhibitor of the upstream phosphatidylinositol 3-kinase (PI3K), abrogated such an enhancement of TNF-? protein expression even though its mRNA levels were conversely increased. These findings highlight a novel mechanism for Rg1 to regulate the innate immune response in macrophages through differentially modulating the NF-?B and PI3K/Akt/mTOR pathways. PMID:25179784

Wang, Yao; Liu, Yi; Zhang, Xiao-Yu; Xu, Li-Hui; Ouyang, Dong-Yun; Liu, Kun-Peng; Pan, Hao; He, Jian; He, Xian-Hui

2014-11-01

172

Immune regulation by non-lymphoid cells in transplantation  

PubMed Central

Regulatory cells play a crucial role in the induction and maintenance of tolerance by controlling T cell as well as B and natural killer (NK) cell-mediated immunity. In transplantation, CD4+CD25+forkhead box P3+ T regulatory cells are instrumental in the maintenance of immunological tolerance, as are several other T cell subsets such as NK T cells, double negative CD3+ T cells, ?? T cells, interleukin-10-producing regulatory type 1 cells, transforming growth factor-?-producing T helper type 3 cells and CD8+CD28? cells. However, not only T cells have immunosuppressive properties, as it is becoming increasingly clear that both T and non-T regulatory cells co-operate and form a network of cellular interactions controlling immune responses. Non-T regulatory cells include tolerogenic dendritic cells, plasmacytoid dendritic cells, mesenchymal stem cells, different types of stem cells, various types of alternatively activated macrophages and myeloid-derived suppressor cells. Here, we review the mechanism of action of these non-lymphoid regulatory cells as they relate to the induction or maintenance of tolerance in organ transplantation. PMID:19196251

Dugast, A-S; Vanhove, B

2009-01-01

173

Establishment of a leukocyte cell line derived from peritoneal macrophages of fish, Labeo rohita (Hamilton, 1822).  

PubMed

A continuous leukocyte cell line with phagocytic activity was established from peritoneal macrophages of rohu, Labeo rohita (LRPM). LRPM was initiated from adherent mononuclear leukocytes isolated from peritoneal cavity of rohu, without use of any growth factors or feeder cells. These cells exhibited maximum growth at 30 °C in L-15 medium containing 20 % foetal bovine serum, and has been subcultured for more than 60 passages till date. The cells showed 85 % viability after 6 months of storage in liquid nitrogen. The species of origin of the LRPM was confirmed by the amplification and sequencing of 655 bp fragment of cytochrome oxidase subunit I of mitochondrial DNA. Functionally, LRPM showed phagocytic activity of yeast cells and fluorescent latex beads as evaluated by phase contrast and scanning electron microscopy, respectively. Immuno-modulators such as bacterial lipopolysaccharide and phorbol myristate acetate resulted in functional activation of LRPM; and enhanced their microbicidal activity through release of reactive oxygen species and nitric oxide. Culture supernatant from activated cells also revealed lysozyme activity. Cells of LRPM were positive for alpha-naphthyl acetate esterase enzyme indicating macrophage lineage. Our results indicate that this cell line can be a useful in vitro tool to study the role of macrophages in teleost immune system and to evaluate the effects of new aquaculture drugs. The LRPM cell line represents the first reported leukocyte cell line of peritoneal origin from any freshwater species of fish. PMID:24248274

Awasthi, Abhishek; Rathore, Gaurav; Sood, Neeraj; Khan, M Y; Lakra, W S

2015-01-01

174

Macrophage characteristics of stem cells revealed by transcriptome profiling  

SciTech Connect

We previously showed that the phenotypes of adipocyte progenitors and macrophages were close. Using functional analyses and microarray technology, we first tested whether this intriguing relationship was specific to adipocyte progenitors or could be shared with other progenitors. Measurements of phagocytic activity and gene profiling analysis of different progenitor cells revealed that the latter hypothesis should be retained. These results encouraged us to pursue and to confirm our analysis with a gold-standard stem cell population, embryonic stem cells or ESC. The transcriptomic profiles of ESC and macrophages were clustered together, unlike differentiated ESC. In addition, undifferentiated ESC displayed higher phagocytic activity than other progenitors, and they could phagocytoze apoptotic bodies. These data suggest that progenitors and stem cells share some characteristics of macrophages. This opens new perspectives on understanding stem cell phenotype and functionalities such as a putative role of stem cells in tissue remodeling by discarding dead cells but also their immunomodulation or fusion properties.

Charriere, Guillaume M. [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France); Cousin, Beatrice [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France); Arnaud, Emmanuelle [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France); Saillan-Barreau, Corinne [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France); Andre, Mireille [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France); Massoudi, Ali [UMR 6543 CNRS, Universite de Nice-Sophia Antipolis, Faculte des Sciences, Parc Valrose, 06108 Nice Cedex 2 (France); Dani, Christian [UMR 6543 CNRS, Universite de Nice-Sophia Antipolis, Faculte des Sciences, Parc Valrose, 06108 Nice Cedex 2 (France); Penicaud, Luc [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France); Casteilla, Louis [UMR 5018 CNRS-UPS, IFR31, Bat L1, CHU Rangueil, 31059 Toulouse Cedex 9 (France)]. E-mail: casteil@toulouse.inserm.fr

2006-10-15

175

Upregulation of Retinal Dehydrogenase 2 in Alternatively Activated Macrophages during Retinoid-dependent Type-2 Immunity to Helminth Infection in Mice  

PubMed Central

Although the vitamin A metabolite retinoic acid (RA) plays a critical role in immune function, RA synthesis during infection is poorly understood. Here, we show that retinal dehydrogenases (Raldh), required for the synthesis of RA, are induced during a retinoid-dependent type-2 immune response elicited by Schistosoma mansoni infection, but not during a retinoid-independent anti-viral immune response. Vitamin A deficient mice have a selective defect in TH2 responses to S. mansoni, but retained normal LCMV specific TH1 responses. A combination of in situ imaging, intra-vital imaging, and sort purification revealed that alternatively activated macrophages (AAM?) express high levels of Raldh2 during S. mansoni infection. IL-4 induces Raldh2 expression in bone marrow-derived macrophages in vitro and peritoneal macrophages in vivo. Finally, in vivo derived AAM? have an enhanced capacity to induce Foxp3 expression in CD4+ cells through an RA dependent mechanism, especially in combination with TGF-?. The regulation of Raldh enzymes during infection is pathogen specific and reflects differential requirements for RA during effector responses. Specifically, AAM? are an inducible source of RA synthesis during helminth infections and TH2 responses that may be important in regulating immune responses. PMID:22927819

Broadhurst, Mara J.; Leung, Jacqueline M.; Lim, K. C.; Girgis, Natasha M.; Gundra, Uma Mahesh; Fallon, Padraic G.; Premenko-Lanier, Mary; McKerrow, James H.; McCune, Joseph M.; Loke, P'ng

2012-01-01

176

Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response  

PubMed Central

Mobilization of the T-cell response against cancer has the potential to achieve long-lasting cures. However, it is not known how to harness antigen-presenting cells optimally to achieve an effective antitumor T-cell response. In this study, we show that anti-CD47 antibody–mediated phagocytosis of cancer by macrophages can initiate an antitumor T-cell immune response. Using the ovalbumin model antigen system, anti-CD47 antibody–mediated phagocytosis of cancer cells by macrophages resulted in increased priming of OT-I T cells [cluster of differentiation 8-positive (CD8+)] but decreased priming of OT-II T cells (CD4+). The CD4+ T-cell response was characterized by a reduction in forkhead box P3-positive (Foxp3+) regulatory T cells. Macrophages following anti-CD47–mediated phagocytosis primed CD8+ T cells to exhibit cytotoxic function in vivo. This response protected animals from tumor challenge. We conclude that anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer but also can initiate an antitumor cytotoxic T-cell immune response. PMID:23690610

Tseng, Diane; Volkmer, Jens-Peter; Willingham, Stephen B.; Contreras-Trujillo, Humberto; Fathman, John W.; Fernhoff, Nathaniel B.; Seita, Jun; Inlay, Matthew A.; Weiskopf, Kipp; Miyanishi, Masanori; Weissman, Irving L.

2013-01-01

177

Tick saliva regulates migration, phagocytosis, and gene expression in the macrophage-like cell line, IC-21.  

PubMed

We studied the effects of tick saliva on cell migration, cell signaling, phagocytosis, and gene expression in the murine macrophage cell line, IC-21. Saliva increased both basal- and platelet-derived growth factor (PDGF)-stimulated migration in IC-21 cells. However, saliva did not affect PDGF-stimulated extracellular signal-regulated kinase (ERK) activity. Zymosan-mediated interleukin-1 receptor associated kinase (IRAK) activity increased when cells were pretreated with saliva. Saliva suppressed phagocytosis of zymosan particles by IC-21 cells. An RT(2) Profiler™ PCR Array revealed that saliva regulates gene expression in a manner consistent with an immune response skewed toward a Th2 reaction, which is characterized by production of anti-inflammatory cytokines IL-4 and IL-10. Our results using IC-21 cells suggest that Dermacentor variabilis has evolved a mechanism for regulating macrophage function, which may contribute to the tick's ability to modulate immune function. PMID:21145320

Kramer, Carolyn D; Poole, Nina M; Coons, Lewis B; Cole, Judith A

2011-03-01

178

Multiple Defects of Immune Cell Function in Mice with Disrupted Interferon-gamma Genes  

Microsoft Academic Search

Interferon-gamma (IFN-gamma) is a pleiotrophic cytokine with immunomodulatory effects on a variety of immune cells. Mice with a targeted disruption of the IFN-gamma gene were generated. These mice developed normally and were healthy in the absence of pathogens. However, mice deficient in IFN-gamma had impaired production of macrophage antimicrobial products and reduced expression of macrophage major histocompatibility complex class II

Dyana K. Dalton; Sharon Pitts-Meek; Satish Keshav; Irene S. Figari; Allan Bradley; Timothy A. Stewart

1993-01-01

179

Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.  

PubMed

The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (Fc?RI) and the low-affinity IgG-binding Fc receptor (Fc?RIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity. PMID:24430180

Gül, Nuray; Babes, Liane; Siegmund, Kerstin; Korthouwer, Rianne; Bögels, Marijn; Braster, Rens; Vidarsson, Gestur; ten Hagen, Timo L M; Kubes, Paul; van Egmond, Marjolein

2014-02-01

180

Impact of carbon nanotubes and graphene on immune cells  

PubMed Central

It has been recently proposed that nanomaterials, alone or in concert with their specific biomolecular conjugates, can be used to directly modulate the immune system, therefore offering a new tool for the enhancement of immune-based therapies against infectious disease and cancer. Here, we revised the publications on the impact of functionalized carbon nanotubes (f-CNTs), graphene and carbon nanohorns on immune cells. Whereas f-CNTs are the nanomaterial most widely investigated, we noticed a progressive increase of studies focusing on graphene in the last couple of years. The majority of the works (56%) have been carried out on macrophages, following by lymphocytes (30% of the studies). In the case of lymphocytes, T cells were the most investigated (22%) followed by monocytes and dendritic cells (7%), mixed cell populations (peripheral blood mononuclear cells, 6%), and B and natural killer (NK) cells (1%). Most of the studies focused on toxicity and biocompatibility, while mechanistic insights on the effect of carbon nanotubes on immune cells are generally lacking. Only very recently high-throughput gene-expression analyses have shed new lights on unrecognized effects of carbon nanomaterials on the immune system. These investigations have demonstrated that some f-CNTs can directly elicitate specific inflammatory pathways. The interaction of graphene with the immune system is still at a very early stage of investigation. This comprehensive state of the art on biocompatible f-CNTs and graphene on immune cells provides a useful compass to guide future researches on immunological applications of carbon nanomaterials in medicine. PMID:24885781

2014-01-01

181

Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules.  

PubMed Central

Alveolar macrophages, resident phagocytic cells in the lung that derive from peripheral blood monocytes, are paradoxically ineffective in presenting antigen to T cells. We found that antigen presentation by alveolar macrophages could be restored by the addition of anti-CD28 mAb to cultures of T cells and macrophages, indicating that costimulation by alveolar macrophages via the CD28 pathway was defective. In addition, we found that alveolar macrophages activated with IFN-gamma failed to express B7-1 or B7-2 antigens, which normally ligate CD28 on T cells and provide a costimulatory signal required for the activation of T cells. These observations are the first to demonstrate the inability of a "professional" antigen-presenting cell type to effectively express the costimulatory molecules B7-1 and B7-2. Inasmuch as immune reactions within the lung are inevitably associated with inflammatory injury to pulmonary tissue, these observations suggest that reduced expression of B7-1 and B7-2 by alveolar macrophages may be advantageous, as a critical mechanism involved in the induction of peripheral tolerance to the abundance of antigens to which mucosal tissues are continuously exposed. PMID:7533793

Chelen, C J; Fang, Y; Freeman, G J; Secrist, H; Marshall, J D; Hwang, P T; Frankel, L R; DeKruyff, R H; Umetsu, D T

1995-01-01

182

Burkholderia mallei and Burkholderia pseudomallei stimulate differential inflammatory responses from human alveolar type II cells (ATII) and macrophages  

PubMed Central

Alveolar type II pneumocytes (ATII) and alveolar macrophages (AM) play a crucial role in the lung's innate immune response. Burkholderia pseudomallei (BP) and Burkholderia mallei (BM) are facultative Gram-negative bacilli that cause melioidosis and glanders, respectively. The inhalation of these pathogens can cause lethal disease and death in humans. We sought to compare the pathogenesis of and host responses to BP and BM through contact with human primary ATII cells and monocytes-derived macrophages (MDM). We hypothesized that because BP and BM induce different disease outcomes, each pathogen would induce distinct, unique host immune responses from resident pulmonary cells. Our findings showed that BP adhered readily to ATII cells compared to BM. BP, but not BM, was rapidly internalized by macrophages where it replicated to high numbers. Further, BP-induced significantly higher levels of pro-inflammatory cytokine secretion from ATII cells (IL-6, IL-8) and macrophages (IL-6, TNF?) at 6 h post-infection compared to BM (p < 0.05). Interestingly, BM-induced the anti-inflammatory cytokine, IL-10, in ATII cells and macrophages at 6 h post-infection, with delayed induction of inflammatory cytokines at 24 h post-infection. Because BP is flagellated and produces LPS, we confirmed that it stimulated both Toll-like receptor (TLR) 4 and TLR5 via NF-?b activation while the non-flagellated BM stimulated only TLR4. These data show the differences in BP and BM pathogenicity in the lung when infecting human ATII cells and macrophages and demonstrate the ability of these pathogens to elicit distinct immune responses from resident lung cells which may open new targets for therapeutic intervention to fight against these pathogens. PMID:23293773

Lu, Richard; Popov, Vsevolod; Patel, Jignesh; Eaves-Pyles, Tonyia

2012-01-01

183

MicroRNAs Transfer from Human Macrophages to Hepato-Carcinoma Cells and Inhibit Proliferation  

PubMed Central

Recent research has indicated a new mode of intercellular communication facilitated by the movement of RNA between cells. There is evidence that RNA can transfer between cells in a multitude of ways, including in complex with proteins, lipids or in vesicles including apoptotic bodies and exosomes. However, there remains little understanding of the function of nucleic acid transfer between human cells. Here, we report that human macrophages transfer microRNAs (miRNAs) to hepato-carcinoma cells (HCCs) in a manner that required intercellular contact and involved gap junctions. Two specific miRNAs efficiently transferred between these cells - miR-142 and miR-223 - both endogenously expressed in macrophages and not HCCs. Transfer of these miRNAs influenced post-transcriptional regulation of proteins in HCCs, including decreased expression of reporter proteins and endogenously expressed stathmin-1 and insulin-like growth factor-1 receptor. Importantly, transfer of miRNAs from macrophages functionally inhibited proliferation of these cancerous cells. Thus, these data lead us to propose that intercellular transfer of miRNA from immune cells could serve as a new defense against unwanted cell proliferation or tumor growth. PMID:24227773

Aucher, Anne; Rudnicka, Dominika; Davis, Daniel M.

2013-01-01

184

Prostaglandin E2 in tick saliva regulates macrophage cell migration and cytokine profile  

PubMed Central

Background Ticks are obligate hematophagous ectoparasites that suppress the host’s immune and inflammatory responses by secreting immuno-modulatory and anti-inflammatory molecules in their saliva. In previous studies we have shown that tick salivary gland extract (SGE) and saliva from Dermacentor variabilis have distinct effects on platelet-derived growth factor (PDGF)-stimulated IC-21 macrophage and NIH3T3-L1 fibroblast migration. Since tick saliva contains a high concentration of prostaglandin E2 (PGE2), a potent modulator of inflammation, we used a PGE2 receptor antagonist to evaluate the role of PGE2 in the different migratory responses induced by saliva and its impact on macrophage cytokine profile. Methods Adult ticks were fed on female New Zealand white rabbits for 5-8 days. Female ticks were stimulated with dopamine/theophylline to induce salivation and saliva was pooled. Competitive enzyme immunoassays (EIA) were used to measure saliva PGE2 content and the changes in macrophage intracellular cyclic adenosine monophosphate (cAMP) levels. The effects of tick saliva on macrophage and fibroblast migration were assessed in the absence and presence of the PGE2 receptor antagonist, AH 6809, using blind well chamber assays. A cytokine antibody array was used to examine the effects of tick saliva on macrophage cytokine secretion. Statistical significance was determined by one-way ANOVA; Student Newman-Kuels post-test was used for multiple comparisons. Results The saliva-induced increase in PDGF-stimulated macrophage migration was reversed by AH 6809. The inhibition of PDGF-stimulated fibroblast migration by saliva was also antagonist-sensitive. Tick saliva induced macrophages to secrete copious amounts of PGE2, and conditioned medium from these cells caused an AH 6809-sensitive inhibition of stimulated fibroblast migration, showing that macrophages can regulate fibroblast activity. We show that tick saliva decreased the secretion of the pro-inflammatory cytokines regulated and normal T cell expressed and secreted (RANTES/CCL5), tumor necrosis factor-alpha (TNF-?), and soluble TNF receptor I (sTNFRI) through a PGE2-dependent mechanism mediated by cAMP. Saliva had similar effects on lipopolysaccharide (LPS) stimulated macrophages. Conclusions Our data show that ticks utilize salivary PGE2 to subvert the ability of macrophages to secrete pro-inflammatory mediators and recruit fibroblasts to the feeding lesion, therefore inhibiting wound healing. PMID:24025197

2013-01-01

185

Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes\\/macrophages  

Microsoft Academic Search

Nuclear factor of activated T cells (NFATs) are crucial transcription factors that tightly control proinflammatory cytokine expression for adaptive immunity in T and B lymphocytes. However, little is known about the role of NFATs for innate immunity in macrophages. In this study, we report that NFAT is required for Toll-like receptor (TLR)-initiated innate immune responses in bone marrow-derived macrophages (BMMs).

Hiroshi Minematsu; Mike J. Shin; Ayse B. Celil Aydemir; Kyung-Ok Kim; Saqib A. Nizami; Gook-Jin Chung; Francis Young-In Lee

2011-01-01

186

Diacylglycerol kinases in immune cell function and self-tolerance  

PubMed Central

Summary Both diacylglycerol (DAG) and phosphatidic acid (PA) are important second messengers involved in signal transduction from many immune cell receptors and can be generated and metabolized through multiple mechanisms. Recent studies indicate that diacylglycerol kinases (DGKs), the enzymes that catalyze phosphorylation of DAG to produce PA, play critical roles in regulating the functions of multiple immune cell lineages. In T cells, two DGK isoforms, ? and ?, inhibit DAG-mediated signaling following T cell receptor engagement and prevent T cell hyperactivation. DGK? and ? synergistically promote T cell anergy and are critical for T cell tolerence. In mast cells, DGK? plays differential roles in their activation by promoting degranulation but attenuating cytokine production following enagement of the high affinity receptor for IgE. In dendritic cells and macrophages, DGK? positively regulates Toll-like receptor-induced proinflammatory cytokine production through its product PA, and is critical for host defense against Toxoplama gondii infection. These studies demonstrate pivotal roles of DGKs in regulating immune cell function by acting both as signal terminator and initiator. PMID:18759932

Zhong, Xiao-Ping; Guo, Rishu; Zhou, Houde; Liu, Chenghu; Wan, Chi-Keung

2012-01-01

187

Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages.  

PubMed

Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV. PMID:24726877

Coulombe, François; Jaworska, Joanna; Verway, Mark; Tzelepis, Fanny; Massoud, Amir; Gillard, Joshua; Wong, Gary; Kobinger, Gary; Xing, Zhou; Couture, Christian; Joubert, Philippe; Fritz, Jörg H; Powell, William S; Divangahi, Maziar

2014-04-17

188

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus.  

PubMed

Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease - the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. PMID:25311810

Behar, Samuel M; Carpenter, Stephen M; Booty, Matthew G; Barber, Daniel L; Jayaraman, Pushpa

2014-12-01

189

Macrophages and Leydig Cells in Testicular Biopsies of Azoospermic Men  

PubMed Central

A number of studies have indicated that testicular macrophages play an important role in regulating steroidogenesis of Leydig cells and maintain homeostasis within the testis. The current paper deals with macrophages (CD68 positive cells) and Leydig cells in patients with nonobstructive azoospermia (NOA). Methods employed included histological analysis on semi- and ultrathin sections, immunohistochemistry, morphometry, and hormone analysis in the blood serum. Histological analysis pointed out certain structural changes of macrophages and Leydig cells in NOA group of patients when compared to controls. In the testis interstitium, an increased presence of CD68 positive cells has been noted. Leydig cells in NOA patients displayed a kind of a mosaic picture across the same bioptic sample: both normal and damaged Leydig cells with pronounced vacuolisation and various intensity of expression of testosterone have been observed. Stereological analysis indicated a significant increase in volume density of both CD68 positive and vacuolated Leydig cells and a positive correlation between the volume densities of these cell types. The continuous gonadotropin overstimulation of Leydig cells, together with a negative paracrine action of macrophages, could result in the damage of steroidogenesis and deficit of testosterone in situ. PMID:24895614

Goluža, Trpimir; Cvetko, Jessica; Bernat, Maja Marija; Kasum, Miro; Kaštelan, Željko; Ježek, Davor

2014-01-01

190

Cyclooxygenase-2 deficiency in macrophages leads to defective p110? PI3K signaling and impairs cell adhesion and migration.  

PubMed

Cyclooxygenase (Cox)-2 dependent PGs modulate several functions in many pathophysiological processes, including migration of immune cells. In this study, we addressed the role of Cox-2 in macrophage migration by using in vivo and in vitro models. Upon thioglycolate challenge, CD11b(+) F4/80(+) macrophages showed a diminished ability to migrate to the peritoneal cavity in cox-2(-/-) mice. In vivo migration of cox-2(-/-) macrophages from the peritoneal cavity to lymph nodes, as well as cell adhesion to the mesothelium, was reduced in response to LPS. In vitro migration of cox-2(-/-) macrophages toward MCP-1, RANTES, MIP-1?, or MIP-1?, as well as cell adhesion to ICAM-1 or fibronectin, was impaired. Defects in cell migration were not due to changes in chemokine receptor expression. Remarkably, cox-2(-/-) macrophages showed a deficiency in focal adhesion formation, with reduced phosphorylation of paxillin (Tyr(188)). Interestingly, expression of the p110? catalytic subunit of PI3K was severely reduced in the absence of Cox-2, leading to defective Akt phosphorylation, as well as cdc42 and Rac-1 activation. Our results indicate that the paxillin/p110?-PI3K/Cdc42/Rac1 axis is defective in cox-2(-/-) macrophages, which results in impaired cell adhesion and migration. PMID:23733875

Díaz-Muñoz, Manuel D; Osma-García, Inés C; Iñiguez, Miguel A; Fresno, Manuel

2013-07-01

191

Hydrogen Peroxide Produced by Oral Streptococci Induces Macrophage Cell Death  

PubMed Central

Hydrogen peroxide (H2O2) produced by members of the mitis group of oral streptococci plays important roles in microbial communities such as oral biofilms. Although the cytotoxicity of H2O2 has been widely recognized, the effects of H2O2 produced by oral streptococci on host defense systems remain unknown. In the present study, we investigated the effect of H2O2 produced by Streptococcus oralis on human macrophage cell death. Infection by S. oralis was found to stimulate cell death of a THP-1 human macrophage cell line at multiplicities of infection greater than 100. Catalase, an enzyme that catalyzes the decomposition of H2O2, inhibited the cytotoxic effect of S. oralis. S. oralis deletion mutants lacking the spxB gene, which encodes pyruvate oxidase, and are therefore deficient in H2O2 production, showed reduced cytotoxicity toward THP-1 macrophages. Furthermore, H2O2 alone was capable of inducing cell death. The cytotoxic effect seemed to be independent of inflammatory responses, because H2O2 was not a potent stimulator of tumor necrosis factor-? production in macrophages. These results indicate that streptococcal H2O2 plays a role as a cytotoxin, and is implicated in the cell death of infected human macrophages. PMID:23658745

Okahashi, Nobuo; Nakata, Masanobu; Sumitomo, Tomoko; Terao, Yutaka; Kawabata, Shigetada

2013-01-01

192

Neisseria gonorrhoeae Modulates Iron-Limiting Innate Immune Defenses in Macrophages  

PubMed Central

Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. The gonococcus can survive extracellularly and intracellularly, but in both environments the bacteria must acquire iron from host proteins for survival. However, upon infection the host uses a defensive response by limiting the bioavailability of iron by a number of mechanisms including the enhanced expression of hepcidin, the master iron-regulating hormone, which reduces iron uptake from the gut and retains iron in macrophages. The host also secretes the antibacterial protein NGAL, which sequesters bacterial siderophores and therefore inhibits bacterial growth. To learn whether intracellular gonococci can subvert this defensive response, we examined expression of host genes that encode proteins involved in modulating levels of intracellular iron. We found that N. gonorrhoeae can survive in association (tightly adherent and intracellular) with monocytes and macrophages and upregulates a panel of its iron-responsive genes in this environment. We also found that gonococcal infection of human monocytes or murine macrophages resulted in the upregulation of hepcidin, NGAL, and NRAMP1 as well as downregulation of the expression of the gene encoding the short chain 3-hydroxybutyrate dehydrogenase (BDH2); BDH2 catalyzes the production of the mammalian siderophore 2,5-DHBA involved in chelating and detoxifying iron. Based on these findings, we propose that N. gonorrhoeae can subvert the iron-limiting innate immune defenses to facilitate iron acquisition and intracellular survival. PMID:24489950

Zughaier, Susu M.; Kandler, Justin L.; Shafer, William M.

2014-01-01

193

Neisseria gonorrhoeae modulates iron-limiting innate immune defenses in macrophages.  

PubMed

Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. The gonococcus can survive extracellularly and intracellularly, but in both environments the bacteria must acquire iron from host proteins for survival. However, upon infection the host uses a defensive response by limiting the bioavailability of iron by a number of mechanisms including the enhanced expression of hepcidin, the master iron-regulating hormone, which reduces iron uptake from the gut and retains iron in macrophages. The host also secretes the antibacterial protein NGAL, which sequesters bacterial siderophores and therefore inhibits bacterial growth. To learn whether intracellular gonococci can subvert this defensive response, we examined expression of host genes that encode proteins involved in modulating levels of intracellular iron. We found that N. gonorrhoeae can survive in association (tightly adherent and intracellular) with monocytes and macrophages and upregulates a panel of its iron-responsive genes in this environment. We also found that gonococcal infection of human monocytes or murine macrophages resulted in the upregulation of hepcidin, NGAL, and NRAMP1 as well as downregulation of the expression of the gene encoding the short chain 3-hydroxybutyrate dehydrogenase (BDH2); BDH2 catalyzes the production of the mammalian siderophore 2,5-DHBA involved in chelating and detoxifying iron. Based on these findings, we propose that N. gonorrhoeae can subvert the iron-limiting innate immune defenses to facilitate iron acquisition and intracellular survival. PMID:24489950

Zughaier, Susu M; Kandler, Justin L; Shafer, William M

2014-01-01

194

Mannose-binding lectin is required for the effective clearance of apoptotic cells by adipose tissue macrophages during obesity.  

PubMed

Obesity is accompanied by the presence of chronic low-grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied wild-type and MBL(-/-) mice rendered obese using a high-fat diet (HFD). Whereas no gross morphological differences were observed in liver, an HFD provoked distinct changes in the adipose tissue morphology of MBL(-/-) mice. In parallel with increased adipocyte size, MBL(-/-) mice displayed an increased influx of macrophages into adipose tissue. Macrophages were polarized toward an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, the absence of MBL did not affect systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in the recognition and clearance of apoptotic adipocytes during obesity. PMID:25008177

Stienstra, Rinke; Dijk, Wieneke; van Beek, Lianne; Jansen, Henry; Heemskerk, Mattijs; Houtkooper, Riekelt H; Denis, Simone; van Harmelen, Vanessa; Willems van Dijk, Ko; Tack, Cees J; Kersten, Sander

2014-12-01

195

The Metastasis-Promoting Roles of Tumor-Associated Immune Cells  

PubMed Central

Tumor metastasis is driven not only by the accumulation of intrinsic alterations in malignant cells, but also by the interactions of cancer cells with various stromal cell components of the tumor microenvironment. In particular, inflammation and infiltration of the tumor tissue by host immune cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells have been shown to support tumor growth in addition to invasion and metastasis. Each step of tumor development, from initiation through metastatic spread, is promoted by communication between tumor and immune cells via the secretion of cytokines, growth factors and proteases that remodel the tumor microenvironment. Invasion and metastasis requires neovascularization, breakdown of the basement membrane, and remodeling of the extracellular matrix for tumor cell invasion and extravasation into the blood and lymphatic vessels. The subsequent dissemination of tumor cells to distant organ sites necessitates a treacherous journey through the vasculature, which is fostered by close association with platelets and macrophages. Additionally, the establishment of the pre-metastatic niche and specific metastasis organ tropism is fostered by neutrophils and bone marrow-derived hematopoietic immune progenitor cells and other inflammatory cytokines derived from tumor and immune cells, which alter the local environment of the tissue to promote adhesion of circulating tumor cells. This review focuses on the interactions between tumor cells and immune cells recruited to the tumor microenvironment, and examines the factors allowing these cells to promote each stage of metastasis. PMID:23515621

Smith, Heath A.; Kang, Yibin

2013-01-01

196

Junin virus infects mouse cells and induces innate immune responses.  

PubMed

Junín virus is the causative agent for Argentine hemorrhagic fever, and its natural host is the New World rodent Calomys musculinus. The virus is transmitted to humans by aerosolization, and it is believed that many of the clinical symptoms are caused by cytokines produced by sentinel cells of the immune system. Here we used the Junín virus vaccine strain Candid 1 to determine whether mouse cells could be used to study virus entry and antiviral innate immune responses. We show that Candid 1 can infect and propagate in different mouse-derived cell lines through a low-pH-dependent, transferrin receptor 1-independent mechanism, suggesting that there is a second entry receptor. In addition, Candid 1 induced expression of the antiviral cytokines tumor necrosis factor alpha and beta interferon in macrophages, and this induction was independent of viral replication. Using Candid 1, as well as virus-like particles bearing the viral glycoprotein, to infect different primary cells and established macrophage cell lines with deletions in the Toll-like receptor (TLR) pathway, we show that TLR2 is a cellular sensor of both the Parodi and Candid 1 viral glycoproteins. Because Junín virus is highly lethal in humans, the use of an experimentally tractable model system, such as the mouse, could provide a better understanding of the antiviral innate cellular responses to Junín virus and the role of these responses in pathogenesis. PMID:21880772

Cuevas, Christian D; Lavanya, Madakasira; Wang, Enxiu; Ross, Susan R

2011-11-01

197

Sepsis-induced potentiation of peritoneal macrophage migration is mitigated by programmed cell death receptor-1 gene deficiency.  

PubMed

The effect of programmed cell death receptor-1 (PD-1) on phagocyte function has not been extensively described. Here we report that experimental mouse sepsis, cecal ligation and puncture (CLP), induced a marked increase in peritoneal macrophage random migration, motility and cell spread, but these changes were lost in the absence of PD-1. Alternatively, phagocytic activity was inversely affected. In vitro cell culture imaging studies, with the macrophage cell line J774, documented that blocking PD-1 with antibody led to aggregation of the cytoskeletal proteins ?-actinin and F-actin. Further experiments looking at ex vivo peritoneal macrophages from mice illustrated that a similar pattern of ?-actinin and F-actin was evident on cells from wild-type CLP mice but not PD-1-/- CLP mouse cells. We also observed that fMLP-induced migration by J774 cells was markedly attenuated using PD-1 blocking antibodies, a nonselective phosphatase inhibitor and a selective Ras-related protein 1 inhibitor. Finally, peritoneal macrophages derived from CLP as opposed to Sham mice demonstrated aspects of both cell surface co-localization with CD11b and internalization of PD-1 within vacuoles independent of CD11b staining. Together, we believe the data support a role for PD-1 in mediating aspects of innate macrophage immune dysfunction during sepsis, heretofore unappreciated. PMID:24247196

Ayala, Alfred; Elphick, Gwendolyn F; Kim, Ye Sul; Huang, Xin; Carreira-Rosario, Arnaldo; Santos, Sadella C; Shubin, Nicholas J; Chen, Yaping; Reichner, Jonathan; Chung, Chun-Shiang

2014-01-01

198

Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses  

PubMed Central

The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications. DOI: http://dx.doi.org/10.7554/eLife.04177.001 PMID:25149452

Chiba, Shiho; Ikushima, Hiroaki; Ueki, Hiroshi; Yanai, Hideyuki; Kimura, Yoshitaka; Hangai, Sho; Nishio, Junko; Negishi, Hideo; Tamura, Tomohiko; Saijo, Shinobu; Iwakura, Yoichiro; Taniguchi, Tadatsugu

2014-01-01

199

Adherent Human Alveolar Macrophages Exhibit a Transient Pro-Inflammatory Profile That Confounds Responses to Innate Immune Stimulation  

PubMed Central

Alveolar macrophages (AM) are thought to have a key role in the immunopathogenesis of respiratory diseases. We sought to test the hypothesis that human AM exhibit an anti-inflammatory bias by making genome-wide comparisons with monocyte derived macrophages (MDM). Adherent AM obtained by bronchoalveolar lavage of patients under investigation for haemoptysis, but found to have no respiratory pathology, were compared to MDM from healthy volunteers by whole genome transcriptional profiling before and after innate immune stimulation. We found that freshly isolated AM exhibited a marked pro-inflammatory transcriptional signature. High levels of basal pro-inflammatory gene expression gave the impression of attenuated responses to lipopolysaccharide (LPS) and the RNA analogue, poly IC, but in rested cells pro-inflammatory gene expression declined and transcriptional responsiveness to these stimuli was restored. In comparison to MDM, both freshly isolated and rested AM showed upregulation of MHC class II molecules. In most experimental paradigms ex vivo adherent AM are used immediately after isolation. Therefore, the confounding effects of their pro-inflammatory profile at baseline need careful consideration. Moreover, despite the prevailing view that AM have an anti-inflammatory bias, our data clearly show that they can adopt a striking pro-inflammatory phenotype, and may have greater capacity for presentation of exogenous antigens than MDM. PMID:22768282

Tomlinson, Gillian S.; Booth, Helen; Petit, Sarah J.; Potton, Elspeth; Towers, Greg J.; Miller, Robert F.; Chain, Benjamin M.; Noursadeghi, Mahdad

2012-01-01

200

Manipulating immune cells for adoptive immunotherapy of cancer.  

PubMed

The immune system can be induced to respond against cancer with some success reported in clinical trials using a range of approaches including vaccines and antibodies. In addition to these approaches, cell based therapies are demonstrating much promise as potential therapies for cancer. In cell therapies autologous patient leukocytes are isolated and manipulated in vitro before transfer back to the patient in adoptive transfer regimens. The majority of approaches utilize conventional T cells or dendritic cells, but a wide variety of other types of leukocytes exist which can possess anti-cancer activity. In this review, we present a brief overview of T cell adoptive cell transfer followed by a review of approaches using alternate lymphocyte subsets and other leukocytes including neutrophils, macrophages and eosinophils. PMID:24534448

Darcy, Phillip K; Neeson, Paul; Yong, Carmen S M; Kershaw, Michael H

2014-04-01

201

Sympathetic glial cells and macrophages develop different responses to Trypanosoma cruzi infection or lipopolysaccharide stimulation  

PubMed Central

Nitric oxide (NO) participates in neuronal lesions in the digestive form of Chagas disease and the proximity of parasitised glial cells and neurons in damaged myenteric ganglia is a frequent finding. Glial cells have crucial roles in many neuropathological situations and are potential sources of NO. Here, we investigate peripheral glial cell response to Trypanosoma cruzi infection to clarify the role of these cells in the neuronal lesion pathogenesis of Chagas disease. We used primary glial cell cultures from superior cervical ganglion to investigate cell activation and NO production after T. cruzi infection or lipopolysaccharide (LPS) exposure in comparison to peritoneal macrophages. T. cruzi infection was greater in glial cells, despite similar levels of NO production in both cell types. Glial cells responded similarly to T. cruzi and LPS, but were less responsive to LPS than macrophages were. Our observations contribute to the understanding of Chagas disease pathogenesis, as based on the high susceptibility of autonomic glial cells to T. cruzi infection with subsequent NO production. Moreover, our findings will facilitate future research into the immune responses and activation mechanisms of peripheral glial cells, which are important for understanding the paradoxical responses of this cell type in neuronal lesions and neuroprotection. PMID:25075784

de Almeida-Leite, Camila Megale; Silva, Isabel Cristina Costa; Galvão, Lúcia Maria da Cunha; Arantes, Rosa Maria Esteves

2014-01-01

202

Induction of Rapid Cell Death by an Environmental Isolate of Legionella pneumophila in Mouse Macrophages  

PubMed Central

Legionella pneumophila, the etiological agent for Legionnaires' disease, is ubiquitous in the aqueous environment, where it replicates as an intracellular parasite of free-living protozoa. Our understanding of L. pneumophila pathogenicity is obtained mostly from study of derivatives of several clinical isolates, which employ almost identical virulent determinants to exploit host functions. To determine whether environmental L. pneumophila isolates interact similarly with the model host systems, we analyzed intracellular replication of several recently isolated such strains and found that these strains cannot productively grow in bone marrow-derived macrophages of A/J mice, which are permissive for all examined laboratory strains. By focusing on one strain called LPE509, we found that its deficiency in intracellular replication in primary A/J macrophages is not caused by the lack of important pathogenic determinants because this strain replicates proficiently in two protozoan hosts and the human macrophage U937 cell. We also found that in the early phase of infection, the trafficking of this strain in A/J macrophages is similar to that of JR32, a derivative of strain Philadelphia 1. Furthermore, infection of these cells by LPE509 caused extensive cell death in a process that requires the Dot/Icm type IV secretion system. Finally, we showed that the cell death is caused neither by the activation of the NAIP5/NLRC4 inflammasome nor by the recently described caspase 11-dependent pathway. Our results revealed that some environmental L. pneumophila strains are unable to overcome the defense conferred by primary macrophages from mice known to be permissive for laboratory L. pneumophila strains. These results also suggest the existence of a host immune surveillance mechanism differing from those currently known in responding to L. pneumophila infection. PMID:23753633

Tao, Lili; Zhu, Wenhan; Hu, Bi-Jie

2013-01-01

203

``Backpack'' Functionalized Living Immune Cells  

NASA Astrophysics Data System (ADS)

We demonstrate that functional polymeric ``backpacks'' built from polyelectrolyte multilayers (PEMs) can be attached to a fraction of the surface area of living, individual lymphocytes. Backpacks containing fluorescent polymers, superparamagnetic nanoparticles, and commercially available quantum dots have been attached to B and T-cells, which may be spatially manipulated using a magnetic field. Since the backpack does not occlude the entire cellular surface from the environment, this technique allows functional synthetic payloads to be attached to a cell that is free to perform its native functions, thereby synergistically utilizing both biological and synthetic functionalities. For instance, we have shown that backpack-modified T-cells are able to migrate on surfaces for several hours following backpack attachment. Possible payloads within the PEM backpack include drugs, vaccine antigens, thermally responsive polymers, nanoparticles, and imaging agents. We will discuss how this approach has broad potential for applications in bioimaging, single-cell functionalization, immune system and tissue engineering, and cell-based therapeutics where cell-environment interactions are critical.

Swiston, Albert; Um, Soong Ho; Irvine, Darrell; Cohen, Robert; Rubner, Michael

2009-03-01

204

CXCR5? T helper cells mediate protective immunity against tuberculosis.  

PubMed

One third of the world's population is infected with Mycobacterium tuberculosis (Mtb). Although most infected people remain asymptomatic, they have a 10% lifetime risk of developing active tuberculosis (TB). Thus, the current challenge is to identify immune parameters that distinguish individuals with latent TB from those with active TB. Using human and experimental models of Mtb infection, we demonstrated that organized ectopic lymphoid structures containing CXCR5+ T cells were present in Mtb-infected lungs. In addition, we found that in experimental Mtb infection models, the presence of CXCR5+ T cells within ectopic lymphoid structures was associated with immune control. Furthermore, in a mouse model of Mtb infection, we showed that activated CD4+CXCR5+ T cells accumulated in Mtb-infected lungs and produced proinflammatory cytokines. Mice deficient in Cxcr5 had increased susceptibility to TB due to defective T cell localization within the lung parenchyma. We demonstrated that CXCR5 expression in T cells mediated correct T cell localization within TB granulomas, promoted efficient macrophage activation, protected against Mtb infection, and facilitated lymphoid follicle formation. These data demonstrate that CD4+CXCR5+ T cells play a protective role in the immune response against TB and highlight their potential use for future TB vaccine design and therapy. PMID:23281399

Slight, Samantha R; Rangel-Moreno, Javier; Gopal, Radha; Lin, Yinyao; Fallert Junecko, Beth A; Mehra, Smriti; Selman, Moises; Becerril-Villanueva, Enrique; Baquera-Heredia, Javier; Pavon, Lenin; Kaushal, Deepak; Reinhart, Todd A; Randall, Troy D; Khader, Shabaana A

2013-02-01

205

CXCR5+ T helper cells mediate protective immunity against tuberculosis  

PubMed Central

One third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). Although most infected people remain asymptomatic, they have a 10% lifetime risk of developing active tuberculosis (TB). Thus, the current challenge is to identify immune parameters that distinguish individuals with latent TB from those with active TB. Using human and experimental models of Mtb infection, we demonstrated that organized ectopic lymphoid structures containing CXCR5+ T cells were present in Mtb-infected lungs. In addition, we found that in experimental Mtb infection models, the presence of CXCR5+ T cells within ectopic lymphoid structures was associated with immune control. Furthermore, in a mouse model of Mtb infection, we showed that activated CD4+CXCR5+ T cells accumulated in Mtb-infected lungs and produced proinflammatory cytokines. Mice deficient in Cxcr5 had increased susceptibility to TB due to defective T cell localization within the lung parenchyma. We demonstrated that CXCR5 expression in T cells mediated correct T cell localization within TB granulomas, promoted efficient macrophage activation, protected against Mtb infection, and facilitated lymphoid follicle formation. These data demonstrate that CD4+CXCR5+ T cells play a protective role in the immune response against TB and highlight their potential use for future TB vaccine design and therapy. PMID:23281399

Slight, Samantha R.; Rangel-Moreno, Javier; Gopal, Radha; Lin, Yinyao; Fallert Junecko, Beth A.; Mehra, Smriti; Selman, Moises; Becerril-Villanueva, Enrique; Baquera-Heredia, Javier; Pavon, Lenin; Kaushal, Deepak; Reinhart, Todd A.; Randall, Troy D.; Khader, Shabaana A.

2013-01-01

206

MyD88 Signaling Pathway Is Involved in Renal Fibrosis by Favoring a TH2 Immune Response and Activating Alternative M2 Macrophages  

PubMed Central

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4+ T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (TH2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished TH2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10+ and CD206+ CD11bhigh cells, at 7 d after surgery. We evaluated the role of a TH2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-? levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and TH1:TH2 balance, as TH2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway. PMID:22777483

Braga, Tarcio Teodoro; Correa-Costa, Matheus; Guise, Yuri Felipe Souza; Castoldi, Angela; de Oliveira, Cassiano Donizetti; Hyane, Meire Ioshie; Cenedeze, Marcos Antonio; Teixeira, Simone Aparecida; Muscara, Marcelo Nicolas; Perez, Katia Regina; Cuccovia, Iolanda Midea; Pacheco-Silva, Alvaro; Gonçalves, Giselle Martins; Camara, Niels Olsen Saraiva

2012-01-01

207

LysoPtdOH Enhances CXCL16 Production Stimulated by LPS from Macrophages and Regulates T cell Migration  

Microsoft Academic Search

As a transmembrane chemokine, CXCL16 has been detected in various tissues and organs under normal and pathological conditions,\\u000a it also plays an important role in macrophages\\/dendritic cells (DC) and T cell interactions and trafficking during inflammation\\u000a and immune responses. LysoPtdOH, a bioactive lipid mediator has been indicated to regulate DC and epithelial functions during\\u000a wound healing and inflammation responses. However,

Shijun Kang; Chunlan Yang; Rongcheng Luo

2008-01-01

208

TLR4 activation under lipotoxic conditions leads to synergistic macrophage cell death through a TRIF-dependent pathway.  

PubMed

Macrophage dysfunction in obesity and diabetes may predispose to the development of diabetic complications, such as infection and impaired healing after tissue damage. Saturated fatty acids, such as palmitate, are present at elevated concentrations in the plasma of patients with metabolic disease and may contribute to the pathogenesis of diabetes and its sequelae. To examine the effect of lipid excess on macrophage inflammatory function, we determined the influence of palmitate on LPS-mediated responses in peritoneal macrophages. Palmitate and LPS led to a profound synergistic cell death response in both primary and RAW 264.7 macrophages. The cell death had features of apoptosis and necrosis and was not dependent on endoplasmic reticulum stress, ceramide generation, or reactive oxygen species production. Instead, we uncovered a macrophage death pathway that required TLR4 signaling via TRIF but was independent of NF-?B, MAPKs, and IRF3. A significant decrease in macrophage lysosomal content was observed early in the death pathway, with evidence of lysosomal membrane damage occurring later in the death response. Overexpression of the transcription factor TFEB, which induces a lysosomal biogenic program, rescued the lysosomal phenotype and improved viability in palmitate- and LPS-treated cells. Our findings provide new evidence for cross-talk between lipid metabolism and the innate immune response that converges on the lysosome. PMID:23275600

Schilling, Joel D; Machkovech, Heather M; He, Li; Diwan, Abhinav; Schaffer, Jean E

2013-02-01

209

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD.  

PubMed

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures and macrophages accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to an increased size and number of iBALT structures, and increased lung compliance and mean linear chord length in wild-type (WT) but not in B cell-deficient mice. The increased accumulation of lung resident macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro coculture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation, which could be inhibited by an anti-IL-10 antibody. In summary, B cell function in iBALT formation seems necessary for macrophage activation and tissue destruction in CS-induced emphysema and possibly provides a new target for therapeutic intervention in COPD. PMID:25128521

John-Schuster, Gerrit; Hager, Katrin; Conlon, Thomas M; Irmler, Martin; Beckers, Johannes; Eickelberg, Oliver; Yildirim, Ali Önder

2014-11-01

210

A novel lipopolysaccharide-binding protein (LBP) gene from sweetfish Plecoglossus altivelis: molecular characterization and its role in the immune response of monocytes/macrophages.  

PubMed

Lipopolysaccharide-binding protein (LBP) belongs to the lipid transfer/LBP (LT-LBP) family, and plays a crucial role in the recognition of bacterial components that modulate cellular signals in phagocytic cells. Although several LBPs have been identified in teleosts, the effects of LBP homologs on teleost phagocytic cells are still obscure. Here, we report the cloning a novel full-length cDNA sequence of LBP-like protein (paLBP) gene from sweetfish, Plecoglossus altivelis. The paLBP cDNA encoded a 464 aa polypeptide, which was closest to that of rainbow smelt (Osmerus mordax). paLBP mRNA was detected mainly in the spleen, liver, and head kidney and levels dramatically increased in various tissues after Listonella anguillarum infection. In contrast to mammalian studies, paLBP mRNA could also be detected in sweetfish monocytes/macrophages. Recombinant paLBP showed LPS-binding activity and Western blot results revealed a significant increase of paLBP in the supernatant of sweetfish monocytes/macrophages challenged with L. anguillarum. Moreover, paLBP neutralization led to up-regulation of IL-1? and TNF-? mRNA as well as respiratory burst activity in sweetfish monocytes/macrophages in response to L. anguillarum or LPS challenge. Therefore, these results suggest that paLBP is an inducible acute-phase protein mediating the immune response of sweetfish monocytes/macrophages upon bacterial challenge. PMID:24594008

Lu, Xin-Jiang; Chu, Chang-Qing; Chen, Qiang; Chen, Jiong

2014-05-01

211

Immune cells and immune-based therapy in pancreatitis.  

PubMed

Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included. PMID:24710635

Xue, Jing; Sharma, Vishal; Habtezion, Aida

2014-05-01

212

Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells.  

PubMed

Parturition is an inflammatory process mediated to a significant extent by macrophages. Progesterone (P4) maintains uterine quiescence in pregnancy, and a proposed functional withdrawal of P4 classically regulated by nuclear progesterone receptors (nPRs) leads to labor. P4 can affect the functions of macrophages despite the reported lack of expression of nPRs in these immune cells. Therefore, in this study we investigated the effects of the activation of the putative membrane-associated PR on the function of macrophages (a key cell for parturition) and discuss the implications of these findings for pregnancy and parturition. In murine macrophage cells (RAW 264.7), activation of mPRs by P4 modified to be active only extracellularly by conjugation to BSA (P4BSA, 1.0×10(-7)?mol/l) caused a pro-inflammatory shift in the mRNA expression profile, with significant upregulation of the expression of cyclooxygenase 2 (COX2 (Ptgs2)), Il1B, and Tnf and downregulation of membrane progesterone receptor alpha (Paqr7) and oxytocin receptor (Oxtr). Pretreatment with PD98059, a MEK1/2 inhibitor, significantly reduced P4BSA-induced expression of mRNA of Il1B, Tnf, and Ptgs2. Inhibition of protein kinase A (PKA) by H89 blocked P4BSA-induced expression of Il1B and Tnf mRNA. P4BSA induced rapid phosphorylation of MEK1/2 and CREB (a downstream target of PKA). This phosphorylation was inhibited by pretreatment with PD98059 and H89, respectively, revealing that MEK1/2 and PKA are two of the components involved in mPR signaling. Taken together, these results indicate that changes in membrane progesterone receptor alpha expression and signaling in macrophages are associated with the inflammatory responses; and that these changes might contribute to the functional withdrawal of P4 related to labor. PMID:25472814

Lu, Jing; Reese, Joshua; Zhou, Ying; Hirsch, Emmet

2015-02-01

213

Radiation exposure induces inflammasome pathway activation in immune cells.  

PubMed

Radiation exposure induces cell and tissue damage, causing local and systemic inflammatory responses. Because the inflammasome pathway is triggered by cell death and danger-associated molecular patterns, we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase-1 detection in cells. Time course analysis showed the appearance of cleaved caspase-1 in cells by day 1 and sustained expression until day 7 after radiation. Also, cells showing inflammasome activation coexpressed the cell surface apoptosis marker annexin V. The role of caspase-1 as a trigger for hematopoietic cell losses after radiation was studied in caspase-1(-/-) mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase-1(-/-) mice than in control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase-1 activation in cells. Finally, we demonstrate that radiation-induced caspase-1 activation occurs by a Nod-like receptor family protein 3-independent mechanism because radiation-exposed Nlrp3(-/-) mice showed caspase-1 activation profiles that were indistinguishable from those of wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation. PMID:25539818

Stoecklein, Veit M; Osuka, Akinori; Ishikawa, Shizu; Lederer, Madeline R; Wanke-Jellinek, Lorenz; Lederer, James A

2015-02-01

214

Glycosylation in immune cell trafficking  

PubMed Central

Summary Leukocyte recruitment encompasses cell adhesion and activation steps that enable circulating leukocytes to roll, arrest, and firmly adhere on the endothelial surface before they extravasate into distinct tissue locations. This complex sequence of events relies on adhesive interactions between surface structures on leukocytes and endothelial cells and also on signals generated during the cell-cell contacts. Cell surface glycans play a crucial role in leukocyte recruitment. Several glycosyltransferases such as ?1,3 fucosyltransferases, ?2,3 sialyltransferases, core 2 N-acetylglucosaminlytransferases, ?1,4 galactosyltransferases and polypeptide N-acetylgalactosaminyltransferases have been implicated in the generation of functional selectin ligands that mediate leukocyte rolling via binding to selectins. Recent evidence also suggests a role of ?2,3 sialylated carbohydrate determinants in triggering chemokine-mediated leukocyte arrest and influencing ?1 integrin function. Additional mechanisms by galectin- and siglec-dependent processes contribute to the growing number of reports emphasizing the significant role of glycans for the successful recruitment of leukocytes into tissues. Advancing the knowledge on glycan function into appropriate pathology models is likely to suggest interesting new therapeutic strategies in the treatment of immune- and inflammation-mediated diseases. PMID:19594631

Sperandio, Markus; Gleissner, Christian A.; Ley, Klaus

2009-01-01

215

Expression and function of genes encoding cholinergic components in murine immune cells.  

PubMed

It is now evident that acetylcholine (ACh) synthesized by choline acetyltransferase (ChAT) and released from T cells during antigen presentation binds to muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively) on T and B cells or dendritic cells, leading to modulation of their function. In the present study, we used reverse transcription-polymerase chain reaction (RT-PCR) to investigate whether mononuclear leukocytes (MNLs), bone marrow-derived dendritic cells (DCs) and macrophages from C57BL/6J mice express components of the cholinergic system. Expression of ChAT mRNA was detected in MNLs activated with ConA and DCs stimulated with LPS, but not in resting MNLs and DCs or in resting and stimulated macrophages. MNLs, DCs and macrophages all expressed mRNAs encoding the five mAChR subtypes (M(1)-M(5)) and the nAChR alpha2, alpha5, alpha6, alpha7, alpha10 and beta2 subunits. Expression of VIP mRNA was detected in MNLs and macrophages, but not in DCs. MNLs, DCs and macrophages all expressed VIP receptor-1 (VPAC1) and -2 (VPAC2) mRNAs, as well as mRNAs encoding secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related protein (SLURP)-1 and SLURP-2, two endogenous nAChR ligands. These results suggest that the lymphocytic cholinergic system is activated by ACh via mAChR- and nAChR-mediated pathways during antigen presentation between T cells and DCs or macrophages, leading to modulation of immune cell function. Moreover, VIP released from both postganglionic cholinergic neurons and immune cells may play a role in the cholinergic anti-inflammatory reflex, acting via VPAC1 and VPAC2 on immune cells. PMID:17383684

Kawashima, Koichiro; Yoshikawa, Ken; Fujii, Yoshihito X; Moriwaki, Yasuhiro; Misawa, Hidemi

2007-05-30

216

Korean mistletoe lectin (KML-IIU) and its subchains induce nitric oxide (NO) production in murine macrophage cells.  

PubMed

Synthesis of nitric oxide (NO) is one of the important effector functions of innate immune cells. Although several reports have indicated mistletoe lectins induce immune cells to produce cytokines, studies regarding the activities of the lectins in the production of NO have been very limited. Here, we report on the induction of NO synthesis in a murine macrophage cell line, RAW264.7, by Korean mistletoe lectin (KML-IIU). When the macrophage cells were treated with KML-IIU in the presence of a suboptimal concentration of IFN-gamma, NO production was induced in a concentration-dependent manner. Significantly higher levels of NO were induced by subchains of the KML-IIU (A and B), which have lower toxicities, as compared to the hololectin. Furthermore, expression of the inducible nitric oxide synthase (iNOS) gene was elevated in accordance with the level of NO production. When the synthase was inhibited by iNOS inhibitors (L-NIL and L-NAME), NO production was specifically reduced in a concentration-dependent manner. Our studies demonstrate that the KML-IIU and its subchains induce NO production in murine macrophage cells via activation of the iNOS gene expression, suggesting that the KML-IIU subchains may be used as an immunomodulator to enhance the effector functions of innate immune cells. PMID:17940853

Kang, Tae Bong; Yoo, Yung Choon; Lee, Kwan Hee; Yoon, Ho Sup; Her, Erk; Kim, Jong Bae; Song, Seong Kyu

2008-03-01

217

A Brucella Virulence Factor Targets Macrophages to Trigger B-cell Proliferation*  

PubMed Central

Brucella spp. and Trypanosoma cruzi are two intracellular pathogens that have no evolutionary common origins but share a similar lifestyle as they establish chronic infections for which they have to circumvent the host immune response. Both pathogens have a virulence factor (prpA in Brucella and tcPrac in T. cruzi) that induces B-cell proliferation and promotes the establishment of the chronic phase of the infectious process. We show here that, even though PrpA promotes B-cell proliferation, it targets macrophages in vitro and is translocated to the cytoplasm during the intracellular replication phase. We observed that PrpA-treated macrophages induce the secretion of a soluble factor responsible for B-cell proliferation and identified nonmuscular myosin IIA (NMM-IIA) as a receptor required for binding and function of this virulence factor. Finally, we show that the Trypanosoma cruzi homologue of PrpA also targets macrophages to induce B-cell proliferation through the same receptor, indicating that this virulence strategy is conserved between a bacterial and a protozoan pathogen. PMID:23720774

Spera, Juan M.; Herrmann, Claudia K.; Roset, Mara S.; Comerci, Diego J.; Ugalde, Juan E.

2013-01-01

218

Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy  

Microsoft Academic Search

This report describes generation of dendritic cells (DCs) and macrophages from human induced pluripotent stem (iPS) cells. iPS cell-derived DC (iPS-DC) exhibited the morphology of typical DC and function of T-cell stimulation and antigen presentation. iPS-DC loaded with cytomegalovirus (CMV) peptide induced vigorous expansion of CMV-specific autologous CD8+ T cells. Macrophages (iPS-MP) with activity of zymosan phagocytosis and C5a-induced chemotaxis

S Senju; M Haruta; K Matsumura; Y Matsunaga; S Fukushima; T Ikeda; K Takamatsu; A Irie; Y Nishimura

2011-01-01

219

In vivo imaging of immune cell trafficking in cancer.  

PubMed

Tumour establishment, progression and regression can be studied in vivo using an array of imaging techniques ranging from MRI to nuclear-based and optical techniques that highlight the intrinsic behaviour of different cell populations in the physiological context. Clinical in vivo imaging techniques and preclinical specific approaches have been used to study, both at the macroscopic and microscopic level, tumour cells, their proliferation, metastasisation, death and interaction with the environment and with the immune system. Fluorescent, radioactive or paramagnetic markers were used in direct protocols to label the specific cell population and reporter genes were used for genetic, indirect labelling protocols to track the fate of a given cell subpopulation in vivo. Different protocols have been proposed to in vivo study the interaction between immune cells and tumours by different imaging techniques (intravital and whole-body imaging). In particular in this review we report several examples dealing with dendritic cells, T lymphocytes and macrophages specifically labelled for different imaging procedures both for the study of their physiological function and in the context of anti-neoplastic immunotherapies in the attempt to exploit imaging-derived information to improve and optimise anti-neoplastic immune-based treatments. PMID:21170525

Ottobrini, Luisa; Martelli, Cristina; Trabattoni, Daria Lucia; Clerici, Mario; Lucignani, Giovanni

2011-05-01

220

Regulation of T-cell function in lung tissue by pulmonary alveolar macrophages.  

PubMed Central

Collagenase digestion of perfused, lavaged rat lung yields a large population of CD5+ T cells, which on current evidence appear to be recently derived from the peripheral blood pool. Two-colour cytofluorographic analysis indicates that approximately 65% are CD4+ T cells, which are predominantly of the activated/memory phenotype. By limiting dilution analysis, these peripheral lung wall T cells and their airway counterparts isolated by bronchoalveolar lavage, exhibit markedly reduced capacity to proliferate by comparison to peripheral blood T cells. However, intratracheal inoculation of liposomes containing dichloro-methylene-diphosphonate at a dosage shown to eliminate the majority of resident alveolar macrophages (AM) rapidly restores the immunocompetence of these lung T-cell populations. These results are discussed in relation to recent reports that in vivo elimination of AM from rats and mice greatly amplifies immune responses to inhaled antigens, in particular T-memory cell-dependent secondary antibody responses. Images Figure 5 PMID:7903277

Strickland, D H; Thepen, T; Kees, U R; Kraal, G; Holt, P G

1993-01-01

221

Functional CD40 Ligand is Expressed on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages: Implications for CD40CD40 Ligand Signaling in Atherosclerosis  

Microsoft Academic Search

Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 ligand (CD40L), an immunoregulatory signaling molecule heretofore considered largely restricted to recently activated CD4+ T lymphocytes, is expressed by human vascular endothelial cells (EC), smooth muscle cells (SMC), and human macrophages in vitro, and is coexpressed with its receptor CD40 on all three cells types

Francois Mach; Uwe Schonbeck; Galina K. Sukhova; Todd Bourcier; Jean-Yves Bonnefoy; Jordan S. Pober; Peter Libby

1997-01-01

222

Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8+ T Cells To Protect against Histoplasmosis ?  

PubMed Central

We have previously revealed the protective role of CD8+ T cells in host defense against Histoplasma capsulatum in animals with CD4+ T cell deficiency and demonstrated that sensitized CD8+ T cells are restimulated in vitro by dendritic cells that have ingested apoptotic macrophage-associated Histoplasma antigen. Here we show that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently activated functional CD8+ T cells whose contribution was equal to that of CD4+ T cells in protection against Histoplasma challenge. Inhibition of macrophage apoptosis due to inducible nitric oxide synthase (iNOS) deficiency or by caspase inhibitor treatment dampened the CD8+ T cell but not the CD4+ T cell response to pulmonary Histoplasma infection. In mice subcutaneously immunized with viable Histoplasma yeasts whose CD8+ T cells are protective against Histoplasma challenge, there was heavy granulocyte and macrophage infiltration and the infiltrating cells became apoptotic. In mice subcutaneously immunized with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled apoptotic macrophages containing heat-killed Histoplasma, the CFSE-labeled macrophage material was found to localize within dendritic cells in the draining lymph node. Moreover, depleting dendritic cells in immunized CD11c-DTR mice significantly reduced CD8+ T cell activation. Taken together, our results revealed that phagocyte apoptosis in the Histoplasma-infected host is associated with CD8+ T cell activation and that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently evokes a protective CD8+ T cell response. These results suggest that employing apoptotic phagocytes as antigen donor cells is a viable approach for the development of efficacious vaccines to elicit strong CD8+ T cell as well as CD4+ T cell responses to Histoplasma infection. PMID:21911464

Hsieh, Shih-Hung; Lin, Jr-Shiuan; Huang, Juin-Hua; Wu, Shang-Yang; Chu, Ching-Liang; Kung, John T.; Wu-Hsieh, Betty A.

2011-01-01

223

Macrophages enhance tumor-derived autophagosomes (DRibbles)-induced B cells activation by TLR4/MyD88 and CD40/CD40L.  

PubMed

Our previous studies have showed that tumor-derived autophagosomes (termed "DRibbles") induce B cell activation, resulting in antibody production and cytokine secretion. Unexpectedly, we found that unfractionated splenocytes produced a higher level of antibody and cytokine than that of purified B cells. In the current study, we investigated the role of accessory cells in DRibbles-induced B cell activation. We found that cognate macrophages, but not T cells, significantly enhanced the B cell activities. Such an enhancement required cell-cell contact. Furthermore, DRibbles stimulation up-regulated CD40L expression on macrophages, resulting in increased level of CD40 expressed on B cells. The accessory role of macrophages in DRibbles-activated B cells is critically dependent on the CD40/CD40L interaction. In addition, the effects of macrophages were found to be largely dependent on TLR4 and MyD88 signaling pathway. Finally, our results showed that macrophages were able to enhance the antigen presentation function of B cells for specific T cell stimulation. Thus, these results suggest that macrophages play an important accessory role for DRibbles-induced B cell immune function. PMID:25447440

Zhou, Meng; Li, Weixia; Wen, Zhifa; Sheng, Yemeng; Ren, Hongyan; Dong, Huixia; Cao, Meng; Hu, Hong-Ming; Wang, Li-Xin

2015-02-15

224

Low expression of FCGRIIB in macrophages of immune thrombocytopenia-affected individuals.  

PubMed

Immune thrombocytopenia (ITP) is an autoimmune disorder described as autoantibody-mediated platelet deterioration. Platelets with affiliated IgG are targeted for exploitation by Fc receptor-mediated phagocytic cellular material within the reticuloendothelial system. The objective of this research is to investigate the relationship between the appearance of FC gamma receptors (FCGR) IIB and IIIA on macrophages and clinicopathological characteristics in ITP patients. FCGRIIB and FCGRIIIA were recognized by immunohistochemistry staining of 62 samples, including regular (n = 20) and ITP (n = 42) samples. Subsequently, the relationship of FC gamma expression levels to ITP progression and clinicopathological characteristics was statistically reviewed. Furthermore, the relationship between Helicobacter pylori (HP) infection and FC gamma expression was analyzed. IHC staining with the coordinated spleen tissue trial samples showed that expression of FCGRIIB on macrophages of ITP patients was tremendously reduced in comparison to the healthy control group. However, no variance was discovered between the two groups with respect to FCGRIIIA expression. There was no substantial correlation among FCGRIIB and FCGRIIIA expression and patient age and gender. Significant differences were found between HP infection and decreased expression of FCGRIIB, while there was no difference with the expression of FCGRIIIA. Lower expression of FCGRIIB is likely involved in the etiology of ITP. HP infection is correlated with decreased expression of FCGRIIB. A rise in FCGRIIB may serve as a therapeutic target for human ITP treatment or possibly as a biomarker for ITP analysis. PMID:23054650

Wu, Zhong; Zhou, Jin; Prsoon, Pankaj; Wei, Xiaoxia; Liu, Xiaojing; Peng, Bing

2012-11-01

225

Live Imaging of Innate Immune Cell Sensing of Transformed Cells in Zebrafish Larvae: Parallels between Tumor Initiation and Wound Inflammation  

PubMed Central

It has not previously been possible to live image the earliest interactions between the host environment and oncogene-transformed cells as they initiate formation of cancers within an organism. Here we take advantage of the translucency of zebrafish larvae to observe the host innate immune cell response as oncogene-transformed melanoblasts and goblet cells multiply within the larval skin. Our studies indicate activation of leukocytes at very early stages in larvae carrying a transformed cell burden. Locally, we see recruitment of neutrophils and macrophages by 48 h post-fertilization, when transformed cells are still only singletons or doublets, and soon after this we see intimate associations between immune and transformed cells and frequent examples of cytoplasmic tethers linking the two cell types, as well as engulfment of transformed cells by both neutrophils and macrophages. We show that a major component of the signal drawing inflammatory cells to oncogenic HRASG12V-transformed cells is H2O2, which is also a key damage cue responsible for recruiting neutrophils to a wound. Our short-term blocking experiments show that preventing recruitment of immune cells at these early stages results in reduced growth of transformed cell clones and suggests that immune cells may provide a source of trophic support to the transformed cells just as they do at a site of tissue repair. These parallels between the inflammatory responses to transformed cells and to wounds reinforce the suggestion by others that cancers resemble non-healing wounds. PMID:21179501

Feng, Yi; Santoriello, Cristina; Mione, Marina; Hurlstone, Adam; Martin, Paul

2010-01-01

226

Macrophage Infection via Selective Capture of HIV-1-Infected CD4+ T Cells  

PubMed Central

Summary Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir and mediating neurological disorders. Cell-free HIV-1 infection of macrophages is inefficient, in part due to low plasma membrane expression of viral entry receptors. We find that macrophages selectively capture and engulf HIV-1-infected CD4+ T cells leading to efficient macrophage infection. Infected T cells, both healthy and dead or dying, were taken up through viral envelope glycoprotein-receptor-independent interactions, implying a mechanism distinct from conventional virological synapse formation. Macrophages infected by this cell-to-cell route were highly permissive for both CCR5-using macrophage-tropic and otherwise weakly macrophage-tropic transmitted/founder viruses but restrictive for nonmacrophage-tropic CXCR4-using virus. These results have implications for establishment of the macrophage reservoir and HIV-1 dissemination in vivo. PMID:25467409

Baxter, Amy E.; Russell, Rebecca A.; Duncan, Christopher J.A.; Moore, Michael D.; Willberg, Christian B.; Pablos, Jose L.; Finzi, Andrés; Kaufmann, Daniel E.; Ochsenbauer, Christina; Kappes, John C.; Groot, Fedde; Sattentau, Quentin J.

2014-01-01

227

Steroid Hormone Signaling Is Essential to Regulate Innate Immune Cells and Fight Bacterial Infection in Drosophila  

PubMed Central

Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells. PMID:24204269

Regan, Jennifer C.; Brandão, Ana S.; Leitão, Alexandre B.; Mantas Dias, Ângela Raquel; Sucena, Élio; Jacinto, António; Zaidman-Rémy, Anna

2013-01-01

228

Macrophage Contact Dependent and Independent TLR4 Mechanisms Induce ?-Cell Dysfunction and Apoptosis in a Mouse Model of Type 2 Diabetes  

PubMed Central

Type 2 diabetes (T2D) is evolving into a global disease and patients have a systemic low-grade inflammation, yet the role of this inflammation is still not established. One plausible mechanism is enhanced expression and activity of the innate immune system. Therefore, we evaluated the expression and the function of the toll-like receptor 4 (TLR4) on pancreatic ?-cells in primary mouse islets and on the murine ?-cell line MIN6 in the presence or absence of macrophages. Diabetic islets have 40% fewer TLR4 positive ?-cells, but twice the number of TLR4 positive macrophages as compared to healthy islets. Healthy and diabetic islets respond to a TLR4 challenge with enhanced production of cytokines (5–10-fold), while the TLR4 negative ?-cell line MIN6 fails to produce cytokines. TLR4 stimulation induces ?-cell dysfunction in mouse islets, measured as reduced glucose stimulated insulin secretion. Diabetic macrophages from 4-months old mice have acquired a transient enhanced capacity to produce cytokines when stimulated with LPS. Interestingly, this is lost in 6-months old diabetic mice. TLR4 activation alone does not induce apoptosis in islets or MIN-6 cells. In contrast, macrophages mediate TLR4-dependent cell-contact dependent (3-fold) as well as cell-contact independent (2-fold) apoptosis of both islets and MIN-6 cells. Importantly, diabetic macrophages have a significantly enhanced capacity to induce ?-cell apoptosis compared to healthy macrophages. Taken together, the TLR4 responsiveness is elevated in the diabetic islets and mainly mediated by newly recruited macrophages. The TLR4 positive macrophages, in both a cell-contact dependent and independent manner, induce apoptosis of ?-cells in a TLR4 dependent fashion and TLR4 activation directly induces ?-cell dysfunction. Thus, targeting either the TLR4 pathway or the macrophages provides a novel attractive treatment regime for T2D. PMID:24594974

Cucak, Helena; Mayer, Christopher; Tonnesen, Morten; Thomsen, Lise Høj; Grunnet, Lars Groth; Rosendahl, Alexander

2014-01-01

229

Macrophage contact dependent and independent TLR4 mechanisms induce ?-cell dysfunction and apoptosis in a mouse model of type 2 diabetes.  

PubMed

Type 2 diabetes (T2D) is evolving into a global disease and patients have a systemic low-grade inflammation, yet the role of this inflammation is still not established. One plausible mechanism is enhanced expression and activity of the innate immune system. Therefore, we evaluated the expression and the function of the toll-like receptor 4 (TLR4) on pancreatic ?-cells in primary mouse islets and on the murine ?-cell line MIN6 in the presence or absence of macrophages. Diabetic islets have 40% fewer TLR4 positive ?-cells, but twice the number of TLR4 positive macrophages as compared to healthy islets. Healthy and diabetic islets respond to a TLR4 challenge with enhanced production of cytokines (5-10-fold), while the TLR4 negative ?-cell line MIN6 fails to produce cytokines. TLR4 stimulation induces ?-cell dysfunction in mouse islets, measured as reduced glucose stimulated insulin secretion. Diabetic macrophages from 4-months old mice have acquired a transient enhanced capacity to produce cytokines when stimulated with LPS. Interestingly, this is lost in 6-months old diabetic mice. TLR4 activation alone does not induce apoptosis in islets or MIN-6 cells. In contrast, macrophages mediate TLR4-dependent cell-contact dependent (3-fold) as well as cell-contact independent (2-fold) apoptosis of both islets and MIN-6 cells. Importantly, diabetic macrophages have a significantly enhanced capacity to induce ?-cell apoptosis compared to healthy macrophages. Taken together, the TLR4 responsiveness is elevated in the diabetic islets and mainly mediated by newly recruited macrophages. The TLR4 positive macrophages, in both a cell-contact dependent and independent manner, induce apoptosis of ?-cells in a TLR4 dependent fashion and TLR4 activation directly induces ?-cell dysfunction. Thus, targeting either the TLR4 pathway or the macrophages provides a novel attractive treatment regime for T2D. PMID:24594974

Cucak, Helena; Mayer, Christopher; Tonnesen, Morten; Thomsen, Lise Høj; Grunnet, Lars Groth; Rosendahl, Alexander

2014-01-01

230

Lactic acid bacterial colonization and human rotavirus infection influence distribution and frequencies of monocytes/macrophages and dendritic cells in neonatal gnotobiotic pigs  

PubMed Central

Despite accumulating knowledge of porcine macrophages and dendritic cells (DCs) from in vitro studies, information regarding monocytes/macrophages and DCs in lymphoid tissues of enteric pathogen-infected neonatal animals in vivo is limited. In this study we evaluated the influence of commensal bacterial [two strains of lactic acid bacteria (LAB), Lactobacillus acidophilus and L. reuteri] colonization and rotavirus infection on distribution and frequencies of monocytes/macrophages and conventional DCs (cDCs) in ileum, spleen and blood. Gnotobiotic pigs were inoculated with LAB and virulent Wa strain human rotavirus (HRV) (LAB+HRV+), HRV only (LAB?HRV+), LAB only (LAB+HRV?) or mock (LAB?HRV?). The cDCs were characterized as SWC3+CD11R1+, whereas monocytes/macrophages were identified as SWC3+CD11R1? by flow cytometry in the gnotobiotic pigs at 10 days of age. Infection with HRV alone activated/recruited significantly more monocytes/macrophages to the intestine than LAB colonization and 56% versus 28% of these cells expressed CD14. Colonization with LAB alone also significantly increased the frequencies of monocytes/macrophages and cDCs and the CD14 expression on monocytes/macrophages in ileum and spleen compared to the controls. LAB colonization plus HRV infection significantly reduced macrophage and cDC frequencies in spleen compared to LAB colonization or HRV infection alone, suggesting that LAB colonization down-regulated HRV? infection-induced monocyte/macrophage activation/recruitment at the systemic lymphoid tissue. These results illustrated the distribution of porcine monocytes/macrophages and cDCs and the frequencies of CD14 expression on these cells in intestinal and systemic lymphoid tissues in the early stage of immune responses to intestinal colonization by LAB versus infection by an enteric pathogen HRV and will facilitate further in vivo studies on functional characterization of these immune cells in neonates. PMID:18006076

Zhang, Wei; Wen, Ke; Azevedo, Marli S.P.; Gonzalez, Ana; Saif, Linda J.; Li, Guohua; Yousef, Ahmed E.; Yuan, Lijuan

2007-01-01

231

Transcription of innate immunity genes and cytokine secretion by canine macrophages resistant or susceptible to intracellular survival of Leishmania infantum.  

PubMed

In this study we assessed the basal transcription of genes associated with innate immunity (i.e. Nramp1, NOD1, NOD2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR9) in canine monocyte-derived macrophages from Leishmania-free dogs. Additionally, secretion of cytokines (IL-10, IL-12, TNF-? and IFN-?) and nitric oxide in culture supernatants of macrophages with higher or lower resistance to intracellular survival of Leishmania infantum was also measured. Constitutive transcription of TLR9 and NOD2 were negligible; NOD1, TLR1, and TLR7 had low levels of transcription, whereas Nramp1 and TLR2, 3, 4, 5, and 6 had higher levels of constitutive transcription in canine monocyte-derived macrophages. There were no significant differences in transcription between macrophages with higher or lower resistance to intracellular survival of L. infantum. Secretion of TNF-? was higher in more resistant macrophages (designated as resistant) at 24h after infection when compared to less resistant macrophages (designated as susceptible), as well as the secretion of IFN-? at 72 h post infection. Secretion of IL-10 was lower in resistant macrophages at 24h after infection. No detectable production of nitric oxide was observed. Interestingly, there was a negative correlation between NOD2 transcript levels and intracellular survival of L. infantum in resistant macrophages. This study demonstrated that decreased intracellular survival of L. infantum in canine macrophages was associated with increased production of TNF-? and IFN-? and decreased production of IL-10; and that constitutive transcription of Nramp1, TLR and NLR does not interfere in intracellular survival of L. infantum. PMID:25466388

Turchetti, Andréia Pereira; da Costa, Luciana Fachini; Romão, Everton de Lima; Fujiwara, Ricardo Toshio; da Paixão, Tatiane Alves; Santos, Renato Lima

2015-01-15

232

Modulation of Murine Macrophage TLR7/8-Mediated Cytokine Expression by Mesenchymal Stem Cell-Conditioned Medium  

PubMed Central

Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) ? and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E2 (PGE2) secreted by the MSCs. PGE2 enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor-?B (NF-?B) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF-?B signaling contributed to the low production of TNF-?. Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection. PMID:24191131

Asami, Takahiro; Ishii, Makoto; Fujii, Hideki; Namkoong, Ho; Tasaka, Sadatomo; Matsushita, Kenichi; Ishii, Ken; Yagi, Kazuma; Fujiwara, Hiroshi; Funatsu, Yohei; Hasegawa, Naoki; Betsuyaku, Tomoko

2013-01-01

233

Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages  

NASA Astrophysics Data System (ADS)

Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity. However, the molecule(s) that confer these cell-type-specific LPS-induced effects remain poorly understood. Here we report that the integrin ?M (CD11b) positively regulates LPS-induced signalling pathways selectively in myeloid dendritic cells but not in macrophages. In dendritic cells, which express lower levels of CD14 and TLR4 than macrophages, CD11b promotes MyD88-dependent and MyD88-independent signalling pathways. In particular, in dendritic cells CD11b facilitates LPS-induced TLR4 endocytosis and is required for the subsequent signalling in the endosomes. Consistent with this, CD11b deficiency dampens dendritic cell-mediated TLR4-triggered responses in vivo leading to impaired T-cell activation. Thus, by modulating the trafficking and signalling functions of TLR4 in a cell-type-specific manner CD11b fine tunes the balance between adaptive and innate immune responses initiated by LPS.

Ling, Guang Sheng; Bennett, Jason; Woollard, Kevin J.; Szajna, Marta; Fossati-Jimack, Liliane; Taylor, Philip R.; Scott, Diane; Franzoso, Guido; Cook, H. Terence; Botto, Marina

2014-01-01

234

Macrophages and ?-cells are responsible for CXCR2-mediated neutrophil infiltration of the pancreas during autoimmune diabetes  

PubMed Central

Autoimmune type 1 diabetes (T1D) development results from the interaction between pancreatic ?-cells, and the innate and the adaptive immune systems culminating with the destruction of the insulin-secreting ?-cells by autoreactive T cells. This diabetogenic course starts during the first postnatal weeks by the infiltration of the pancreatic islets by innate immune cells and particularly neutrophils. Here, we aim to determine the cellular and molecular mechanism leading to the recruitment of this neutrophils in the pancreatic islets of non-obese diabetic (NOD) mice. Here, we show that neutrophil recruitment in the pancreatic islets is controlled by inflammatory macrophages and ?-cells themselves. Macrophages and ?-cells produce the chemokines CXCL1 and CXCL2, recruiting CXCR2-expressing neutrophils from the blood to the pancreatic islets. We further show that pancreatic macrophages secrete IL-1?-inducing CXCR2 ligand production by the ?-cells. Finally, the blockade of neutrophil recruitment at early ages using CXCR2 antagonist dampens the diabetogenic T-cell response and the later development of autoimmune diabetes, supporting the therapeutic potential of this approach. Subject Categories Immunology; Metabolism PMID:24968718

Diana, Julien; Lehuen, Agnès

2014-01-01

235

Hematopoietic stem cells: interplay with immunity  

PubMed Central

Ample evidence indicated that hematopoietic stem cells (HSCs) receive signaling from infection or other immune responses to adjust their differentiation and self-renewal. More recent reports also suggested that, while the bone marrow microenvironment or niche may provide the immune privilege for HSCs, HSCs can present surface immune inhibitors per se to suppress innate immunity and adaptive immunity to evade potential immune surveillance and attack. These findings support the hypothesis that HSCs are capable of interacting with the immune system as signal “receivers” and signal “providers”. On the one hand, HSCs are capable of directly sensing the signals from the immune system through their surface receptors to modulate their self-renewal and differentiation (“in” signaling); on the other hand, HSCs display surface immune inhibitory molecules to evade the attack from the innate and adaptive immune systems (“out” signaling). The continuing investigation of the interplay between HSCs and immunity may lead to the open-up of a new research filed – the immunology of stem cells. PMID:23226622

Zhang, Cheng Cheng

2012-01-01

236

Brominated flame retardants stimulate mouse immune cells in vitro.  

PubMed

Brominated flame retardants (BFRs) are widely used in consumer products. Their toxicological effects as endocrine disruptors have been partly examined. However, their immunological effects have not been elucidated. To evaluate the effects of BFRs on immune responses, we investigated whether BFRs affect phenotypes and the function of immune cells in vitro. Here we examined the commercial pentabromodiphenyl ether mixture (DE-71), octabromodiphenyl ether mixture (DE-79), decabromodiphenyl ether mixture (DE-83R), hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA). Splenocytes and bone marrow (BM) cells were prepared from atopic prone NC/Nga mice. Splenocytes were exposed to each BFR for 24?h. BM cells were cultured with granulocyte macrophage-colony stimulating factor (GM-CSF) for 8?days and BM-derived dendritic cells (BMDCs) were exposed to each BFR for 24?h. In another experiment, BM cells were cultured with GM-CSF in the presence of each BFR for 6?days during BMDC differentiation. After exposure, cell surface molecule expression and cytokine production were investigated. Each BFR increased MHC class II and CD86 expression and interleukin (IL)-4 production in splenocytes. DE-71, HBCD and TBBPA increased T cell receptor (TCR) expression in splenocytes. In both experiments, all BFRs except TBBPA increased DEC205 expression in BMDCs. BMDCs that differentiated in the presence of HBCD showed enhanced MHC class II, CD80, CD86 and CD11c expression. The results demonstrate that some BFRs may stimulate immune cells. BFRs can induce or enhance immune/allergic responses by increasing antigen presentation-related molecule expression and IL-4 production. PMID:22972382

Koike, Eiko; Yanagisawa, Rie; Takigami, Hidetaka; Takano, Hirohisa

2013-12-01

237

Cortisol modulates the induction of inflammatory gene expression in a rainbow trout macrophage cell line.  

PubMed

Glucocorticoid actions on the immune system are diverse and cell type dependent, and little is known about cell type-specific interactions and cross-talk between hormones and cytokines. In this study we have analyzed the gene expression patterns of the rainbow trout macrophage cell line RTS-11 by quantitative PCR, after exposure to combinations of cortisol plus a pro-inflammatory cytokine (e.g. recombinant trout IL-1?, IFN-?), type I IFN or a PAMP (LPS or poly I:C). Several key genes of the inflammatory process were targetted to assess whether any modulation of their expression occurred due to the addition of cortisol to this cell line. Incubation of macrophages for 3 or 6 h with a physiological concentration of cortisol caused a decrease in expression of IL-6 and IL-8, but no significant changes were observed for the other genes examined. Co-stimulation of cortisol with the inflammatory agents resulted in a general suppression of genes related to the inflammatory response. Cortisol inhibited the up-regulation of IL-8 by all the stimulants after 3 h of co-incubation. Suppression of the up-regulation of IL-6 by rIL-1?, rIFN-? and poly I:C, of ?IP by rIFN-? or poly I:C, and of Cox-2 by rIL-1? was seen after 6 h. In contrast, cortisol in combination with the pro-inflammatory agents has a synergistic effect on IL-10 expression, an anti-inflammatory molecule, suggesting that the activation of certain macrophage functions that lead to the resolution of inflammation occurs in fish macrophages in response to cortisol treatment. PMID:20965252

Castro, Rosario; Zou, Jun; Secombes, Christopher J; Martin, Samuel A M

2011-01-01

238

CD4+ T cell-derived IL-10 promotes Brucella abortus persistence via modulation of macrophage function.  

PubMed

Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4(+)CD25(+) T cells to produce the anti-inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro-inflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25(+)CD4(+) T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection. PMID:23818855

Xavier, Mariana N; Winter, Maria G; Spees, Alanna M; Nguyen, Kim; Atluri, Vidya L; Silva, Teane M A; Bäumler, Andreas J; Müller, Werner; Santos, Renato L; Tsolis, Renée M

2013-01-01

239

Dectin-1 induces M1 macrophages and prominent expansion of CD8+IL-17+ cells in pulmonary Paracoccidioidomycosis.  

PubMed

Dectin-1, the innate immune receptor that recognizes ?-glucan, plays an important role in immunity against fungal pathogens. Paracoccidioides brasiliensis, the etiological agent of paracoccidioidomycosis, has a sugar-rich cell wall mainly composed of mannans and glucans. This fact motivated us to use dectin-1-sufficient and -deficient mice to investigate the role of ?-glucan recognition in the immunity against pulmonary paracoccidioidomycosis. Initially, we verified that P. brasiliensis infection reinforced the tendency of dectin-1-deficient macrophages to express an M2 phenotype. This prevalent antiinflammatory activity of dectin-1(-/-) macrophages resulted in impaired fungicidal ability, low nitric oxide production, and elevated synthesis of interleukin 10 (IL-10). Compared with dectin-1-sufficient mice, the fungal infection of dectin-1(-/-) mice was more severe and resulted in enhanced tissue pathology and mortality rates. The absence of dectin-1 has also impaired the production of T-helper type 1 (Th1), Th2, and Th17 cytokines and the activation and migration of T cells to the site of infection. Remarkably, dectin-1 deficiency increased the expansion of regulatory T cells and reduced the differentiation of T cells to the IL-17(+) phenotype, impairing the migration of IL-17(+)CD8(+) T cells and polymorphonuclear cells to infected tissues. In conclusion, dectin-1 exerts an important protective role in pulmonary paracoccidioidomycosis by controlling the innate and adaptive phases of antifungal immunity. PMID:24604821

Loures, Flávio V; Araújo, Eliseu F; Feriotti, Claudia; Bazan, Silvia B; Costa, Tânia A; Brown, Gordon D; Calich, Vera L G

2014-09-01

240

Cell death and DNA damage in peritoneal macrophages of mice (Mus musculus) exposed to inorganic lead.  

PubMed

Lead is a heavy metal of considerable environmental and occupational concern and there is growing evidence that it is toxic to the human immune system. In this regard, this study examined the effect of lead (Pb) exposure to peritoneal macrophages (Mvarphis) of mice (Mus musculus) cultivated in DMEM medium supplemented with fetal bovine serum, in order to investigate cell damage related to cell death. Cells were exposed to two concentrations of inorganic lead [Pb(II)] for 4, 24 and 72h. Cell viability declined during the treatment, with responses including cell death, cellular damage and DNA damage. Cell death images were found in treated cells with an increase in Bax expression, but the inorganic lead failed to induce the loss of membrane asymmetry (Annexin V conjugates), suggesting that cell death was mainly due to necrosis induction. The effects of Pb(II) on the mechanisms of cell death is not completely understood, but the immunosuppression due to DNA damage and Mvarphis death is discussed here. We have previously shown the effect of inorganic lead in mitochondria and phagocytosis in Mvarphis, suggesting here a pathway for the effect of the metal on mechanisms of cell death, also discussing its effects on the immune system. PMID:16757190

Gargioni, R; Filipak Neto, F; Buchi, D F; Randi, M A F; Franco, C R C; Paludo, K S; Pelletier, E; Ferraro, M V M; Cestari, M M; Bussolaro, D; Oliveira Ribeiro, C A

2006-07-01

241

Ongoing cell death and immune influences on regeneration in the vestibular sensory organs  

NASA Technical Reports Server (NTRS)

Hair cells in the vestibular organs of birds have a relatively short life span. Mature hair cells appear to die spontaneously and are then quickly replaced by new hair cells that arise from the division of epithelial supporting cells. A similar regenerative mechanism also results in hair cell replacement after ototoxic damage. The cellular basis of hair cell turnover in the avian ear is not understood. We are investigating the signaling pathways that lead to hair cell death and the relationship between ongoing cell death and cell production. In addition, work from our lab and others has demonstrated that the avian inner ear contains a resident population of macrophages and that enhanced numbers of macrophages are recruited to sites of hair cells lesions. Those observations suggest that macrophages and their secretory products (cytokines) may be involved in hair cell regeneration. Consistent with that suggestion, we have found that treatment with the anti-inflammatory drug dexamethasone reduces regenerative cell proliferation in the avian ear, and that certain macrophage-secreted cytokines can influence the proliferation of vestibular supporting cells and the survival of statoacoustic neurons. Those results suggest a role for the immune system in the process of sensory regeneration in the inner ear.

Warchol, M. E.; Matsui, J. I.; Simkus, E. L.; Ogilive, J. M.

2001-01-01

242

Modulation of macrophage phenotype by cell shape Frances Y. McWhortera,b,1  

E-print Network

Cardiovascular Technology, University of California, Irvine, CA 92697 Edited by Robert Langer, Massachusetts) Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment macrophage subpopulations are clearly observed at different phases of the immune response to infection

Liu, Wendy

243

Mechanisms of NK Cell-Macrophage Bacillus anthracis Crosstalk: A Balance between Stimulation by Spores and Differential Disruption by Toxins  

PubMed Central

NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-? production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non-toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-? production by NK cells in response to B. anthracis spores was: i) contact-dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-? production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-? secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-? secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms. PMID:22253596

Klezovich-Bénard, Maria; Corre, Jean-Philippe; Jusforgues-Saklani, Hélène; Fiole, Daniel; Burjek, Nick; Tournier, Jean-Nicolas; Goossens, Pierre L.

2012-01-01

244

Orchestration of Angiogenesis by Immune Cells  

PubMed Central

It is widely accepted that the tumor microenvironment (TUMIC) plays a major role in cancer and is indispensable for tumor progression. The TUMIC involves many “players” going well beyond the malignant-transformed cells, including stromal, immune, and endothelial cells (ECs). The non-malignant cells can acquire tumor-promoting functions during carcinogenesis. In particular, these cells can “orchestrate” the “symphony” of the angiogenic switch, permitting the creation of new blood vessels that allows rapid expansion and progression toward malignancy. Considerable attention within the context of tumor angiogenesis should focus not only on the ECs, representing a fundamental unit, but also on immune cells and on the inflammatory tumor infiltrate. Immune cells infiltrating tumors typically show a tumor-induced polarization associated with attenuation of anti-tumor functions and generation of pro-tumor activities, among these angiogenesis. Here, we propose a scenario suggesting that the angiogenic switch is an immune switch arising from the pro-angiogenic polarization of immune cells. This view links immunity, inflammation, and angiogenesis to tumor progression. Here, we review the data in the literature and seek to identify the “conductors” of this “orchestra.” We also suggest that interrupting the immune???inflammation???angiogenesis???tumor progression process can delay or prevent tumor insurgence and malignant disease. PMID:25072019

Bruno, Antonino; Pagani, Arianna; Pulze, Laura; Albini, Adriana; Dallaglio, Katiuscia; Noonan, Douglas M.; Mortara, Lorenzo

2014-01-01

245

Porcine spermadhesin PSP-I/PSP-II stimulates macrophages to release a neutrophil chemotactic substance: modulation by mast cells.  

PubMed

The complex of porcine seminal plasma heterodimers I and II (PSP-I/PSP-II), which are heterodimers of glycosylated spermadhesins, is the major component of porcine seminal fluid. The proinflammatory and immunostimulatory activities of this spermadhesin complex suggest its participation in modulation of the uterine immune activity that may ensure reproductive success. Spermadhesin PSP-I/PSP-II induced the migration of neutrophils into the peritoneal cavity of rats via activation of resident cells. In the present study, we have investigated the involvement of macrophages and mast cells in the neutrophil chemotactic activity of PSP-I/PSP-II and the underlying mechanism. Macrophages and mast cells were isolated, cultured, and stimulated with purified PSP-I/PSP-II. Pharmacological modulation was performed using the glucocorticoid dexamethasone, indomethacin (cyclooxygenase inhibitor), MK886 (leukotriene inhibitor), and the supernatant of spermadhesin-stimulated mast cells. Macrophages stimulated with PSP-I/PSP-II released into the culture supernatant a neutrophil chemotactic substance. This activity was partly inhibited by both dexamethasone (85%) and the supernatant of spermadhesin-stimulated mast cells (74%) but not by indomethacin and MK886. An anti-tumor necrosis factor (TNF) alpha antibody neutralized (by 68%) the neutrophil chemotactic activity of PSP-I/PSP-II-stimulated macrophages. An anti-interleukin (IL)-4 antibody blocked the inhibitory activity of spermadhesin-stimulated mast cells on release of a neutrophil chemotactic substance by PSP-I/PSP-II-stimulated macrophages. As a whole, these data indicate that the neutrophil migration-inducing ability of spermadhesin PSP-I/PSP-II involves the release of the inflammatory cytokine TNFalpha by stimulated macrophages and that this activity is modulated by the lymphokine IL-4 liberated by mast cells. The balance between these two cytokines may control onset of the local inflammatory reaction, avoiding excessive neutrophil recruitment that would lead to tissue damage. PMID:12606406

Assreuy, Ana Maria S; Alencar, Nylane M N; Cavada, Benildo S; Rocha-Filho, Duílio R; Feitosa, Regina F G; Cunha, Fernando Q; Calvete, Juan J; Ribeiro, Ronaldo A

2003-05-01

246

Uranyl nitrate-exposed rat alveolar macrophages cell death: Influence of superoxide anion and TNF ? mediators  

SciTech Connect

Uranium compounds are widely used in the nuclear fuel cycle, military and many other diverse industrial processes. Health risks associated with uranium exposure include nephrotoxicity, cancer, respiratory, and immune disorders. Macrophages present in body tissues are the main cell type involved in the internalization of uranium particles. To better understand the pathological effects associated with depleted uranium (DU) inhalation, we examined the metabolic activity, phagocytosis, genotoxicity and inflammation on DU-exposed rat alveolar macrophages (12.5–200 ?M). Stability and dissolution of DU could differ depending on the dissolvent and in turn alter its biological action. We dissolved DU in sodium bicarbonate (NaHCO{sub 3} 100 mM) and in what we consider a more physiological vehicle resembling human internal media: sodium chloride (NaCl 0.9%). We demonstrate that uranyl nitrate in NaCl solubilizes, enters the cell, and elicits its cytotoxic effect similarly to when it is diluted in NaHCO{sub 3}. We show that irrespective of the dissolvent employed, uranyl nitrate impairs cell metabolism, and at low doses induces both phagocytosis and generation of superoxide anion (O{sub 2}{sup ?}). At high doses it provokes the secretion of TNF? and through all the range of doses tested, apoptosis. We herein suggest that at DU low doses O{sub 2}{sup ?} may act as the principal mediator of DNA damage while at higher doses the signaling pathway mediated by O{sub 2}{sup ?} may be blocked, prevailing damage to DNA by the TNF? route. The study of macrophage functions after uranyl nitrate treatment could provide insights into the pathophysiology of uranium?related diseases. -- Highlights: ? Uranyl nitrate effect on cultured macrophages is linked to the doses and independent of its solubility. ? At low doses uranyl nitrate induces generation of superoxide anion. ? At high doses uranyl nitrate provokes secretion of TNF?. ? Uranyl nitrate induces apoptosis through all the range of doses tested.

Orona, N.S. [School of Science and Technology, National University of General Martín, Avda Gral Paz 5445 (1650) San Martín, Buenos Aires (Argentina)] [School of Science and Technology, National University of General Martín, Avda Gral Paz 5445 (1650) San Martín, Buenos Aires (Argentina); Tasat, D.R., E-mail: deborah.tasat@unsam.edu.ar [School of Science and Technology, National University of General Martín, Avda Gral Paz 5445 (1650) San Martín, Buenos Aires (Argentina); School of Dentistry, University of Buenos Aires, M. T. de Alvear 2142 (1122), Buenos Aires (Argentina)

2012-06-15

247

Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells  

Microsoft Academic Search

Apoptotic cells activate homologous complement and are opsonized with iC3b. We assessed the effect of iC3b opsonization upon phagocytosis of apoptotic Jurkat cells by macrophages, which were differentiated from THP-1 cells by treatment with retinoic acid. Macrophage phagocytosis of apoptotic Jurkat cells was enhanced upon incubation of the apoptotic cells with normal human serum. The enhanced macrophage phagocytosis of normal

Fumitake Takizawa; Shoutaro Tsuji; Shigeharu Nagasawa

1996-01-01

248

Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis  

PubMed Central

Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4–neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection. PMID:25180604

Dahdah, Albert; Gautier, Gregory; Attout, Tarik; Fiore, Frédéric; Lebourdais, Emeline; Msallam, Rasha; Daëron, Marc; Monteiro, Renato C.; Benhamou, Marc; Charles, Nicolas; Davoust, Jean; Blank, Ulrich; Malissen, Bernard; Launay, Pierre

2014-01-01

249

Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis.  

PubMed

Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4-neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection. PMID:25180604

Dahdah, Albert; Gautier, Gregory; Attout, Tarik; Fiore, Frédéric; Lebourdais, Emeline; Msallam, Rasha; Daëron, Marc; Monteiro, Renato C; Benhamou, Marc; Charles, Nicolas; Davoust, Jean; Blank, Ulrich; Malissen, Bernard; Launay, Pierre

2014-10-01

250

Some immune cells appear to aid cancer cell growth  

Cancer.gov

The immune system is normally known for protecting the body from illness. But a subset of immune cells appear to be doing more harm than good. A new study from researchers at the University of Michigan Comprehensive Cancer Center found that these cells, called myeloid derived suppressor cells, provide a niche where the cancer stem cells survive.

251

Macrophage Autophagy in Atherosclerosis  

PubMed Central

Macrophages play crucial roles in atherosclerotic immune responses. Recent investigation into macrophage autophagy (AP) in atherosclerosis has demonstrated a novel pathway through which these cells contribute to vascular inflammation. AP is a cellular catabolic process involving the delivery of cytoplasmic contents to the lysosomal machinery for ultimate degradation and recycling. Basal levels of macrophage AP play an essential role in atheroprotection during early atherosclerosis. However, AP becomes dysfunctional in the more advanced stages of the pathology and its deficiency promotes vascular inflammation, oxidative stress, and plaque necrosis. In this paper, we will discuss the role of macrophages and AP in atherosclerosis and the emerging evidence demonstrating the contribution of macrophage AP to vascular pathology. Finally, we will discuss how AP could be targeted for therapeutic utility. PMID:23401644

Maiuri, Maria Chiara; Grassia, Gianluca; Platt, Andrew M.; Carnuccio, Rosa; Ialenti, Armando; Maffia, Pasquale

2013-01-01

252

Mucosal dendritic cells shape mucosal immunity  

PubMed Central

Dendritic cells (DCs) are key modulators that shape the immune system. In mucosal tissues, DCs act as surveillance systems to sense infection and also function as professional antigen-presenting cells that stimulate the differentiation of naive T and B cells. On the basis of their molecular expression, DCs can be divided into several subsets with unique functions. In this review, we focus on intestinal DC subsets and their function in bridging the innate signaling and adaptive immune systems to maintain the homeostasis of the intestinal immune environment. We also review the current strategies for manipulating mucosal DCs for the development of efficient mucosal vaccines to protect against infectious diseases. PMID:24626170

Chang, Sun-Young; Ko, Hyun-Jeong; Kweon, Mi-Na

2014-01-01

253

Regulation of macrophage and dendritic cell responses by their lineage precursors  

PubMed Central

Tissue macrophages and dendritic cells derive from hematopoietic stem cells, which exist in the bone marrow and generate intermediate precursor populations with increasingly restricted lineage potentials. There exists several precursors committed to the macrophage and dendritic cell lineages; these cells exhibit distinct tropism and function and respond differentially in pathophysiologic conditions. In this review, we consider experimental contexts in which macrophage and dendritic cell responses in tissue are not only dictated by the local environment, but also by the quantity and quality of newly recruited lineage precursor cells. Consequently, we discuss whether therapeutic control of macrophage and dendritic cell responses in tissue may be achieved through manipulation of their lineage precursors. PMID:22433183

Cortez-Retamozo, Virna; Etzrodt, Martin; Pittet, Mikael J.

2012-01-01

254

Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10.  

PubMed

Forkhead box P3 (Foxp3)(+) regulatory T (Treg) cells maintain the immune tolerance and prevent inflammatory responses in the periphery. However, the presence of Treg cells in the CNS under steady state has not been studied. Here, for the first time, we show a substantial TCR?? (+) CD4(+) Foxp3(+) T-cell population (cerebral Treg cells) in the rat cerebrum, constituting more than 15% of the cerebral CD4(+) T-cell compartment. Cerebral Treg cells showed an activated/memory phenotype and expressed many Treg-cell signature genes at higher levels than peripheral Treg cells. Consistent with their activated/memory phenotype, cerebral Treg cells robustly restrained the LPS-induced inflammatory responses of brain microglia/macrophages, suggesting a role in maintaining the cerebral homeostasis by inhibiting the neuroinflammation. In addition, brain astrocytes were the helper cells that sustained Foxp3 expression in Treg cells through IL-2/STAT5 signaling, showing that the interaction between astrocytes and Treg cells contributes to the maintenance of Treg-cell identity in the brain. Taken together, our work represents the first study to characterize the phenotypic and functional features of Treg cells in the rat cerebrum. Our data have provided a novel insight for the contribution of Treg cells to the immunosurveillance and immunomodulation in the cerebrum under steady state. PMID:25329858

Xie, Luokun; Choudhury, Gourav Roy; Winters, Ali; Yang, Shao-Hua; Jin, Kunlin

2015-01-01

255

Thyroid signaling in immune organs and cells of the teleost fish rainbow trout (Oncorhynchus mykiss).  

PubMed

Thyroid hormones are involved in modulating the immune system in mammals. In contrast, there is no information on the role played by these hormones in the immune system of teleost fish. Here we provide initial evidence for the presence of active thyroid signaling in immune organs and cells of teleosts. We demonstrate that immune organs (head kidney and spleen) and isolated leukocytes (from head kidney and peripheral blood) of the rainbow trout (Oncorhynchus mykiss) express both thyroid receptor ? (THRA) and ? (THRB). Absolute mRNA levels of THRA were significantly higher than those of THRB. THRA showed higher expression in immune organs and isolated immune cells compared to the reference organ, liver, while THRB showed the opposite. In vivo exposure of trout to triiodothryronine (T3) or the anti-thyroid agent propylthiouracil (PTU) altered THR expression in immune organs and cells. Effect of T3 and PTU over the relative expression of selected marker genes of immune cell subpopulations was also studied. Treatments changed the relative expression of markers of cytotoxic, helper and total T cells (cd4, cd8a, trb), B lymphocytes (mIgM) and macrophages (csf1r). These findings suggest that the immune system of rainbow trout is responsive to thyroid hormones. PMID:24657316

Quesada-García, A; Valdehita, A; Kropf, C; Casanova-Nakayama, A; Segner, H; Navas, J M

2014-05-01

256

Macrophages: Gatekeepers of Tissue Integrity  

PubMed Central

Macrophages form a heterogeneous group of hematopoietic cells that reside in tissues, where they are required to maintain organ integrity. Tissue macrophages contribute to tissue formation, metabolism, homeostasis, and repair. They have a unique ability to sense and respond to tissue damage. They serve as the first line of defense during infection and help promote immune tolerance in the steady state. Although most tissue macrophages share a high phagocytic and degradative potential, they are heterogeneous in origin, as well as in homeostatic function and response to insults. Here, we will discuss recent developments in our understanding of the origin of tissue macrophages and their functional specialization in tissues. PMID:24777851

Lavin, Yonit; Merad, Miriam

2014-01-01

257

1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism.  

PubMed

The vitamin D receptor (VDR) is a hormone nuclear receptor regulating bone and calcium homeostasis. Studies revealing the expression of VDR on immune cells point toward a role for VDR-dependent signaling pathways in immunity. Here we verified the ability of the natural VDR ligand, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to interfere in inflammatory and T cell stimulatory capacity of macrophages, in particular within a chronic inflammatory disease features of experimental type 1 diabetes (T1D). We demonstrated that VDR is constitutively expressed in macrophages and both the levels of VDR and its downstream targets, are clearly induced by 1,25(OH)(2)D(3). In control mice, macrophage programming with 1,25(OH)(2)D(3) partially abrogated the activation-provoked expression of IL-12p40, TNF? and iNOS as well as the effector T cell-recruiting chemokines, CXCL9, CXCL10 and CXCL11. Targeting VDR signaling in macrophages counteracted their T-cell stimulatory ability despite essentially unaltered expression of antigen-presenting and costimulatory molecules. Furthermore, even in non-obese diabetic (NOD) mice, where macrophages/monocytes featured a heightened responsiveness toward danger signals and a superior T cell stimulatory capacity, 1,25(OH)(2)D(3) successfully curtailed these basic macrophage-mediated functions. Interestingly, the inhibitory action of the active compound was associated with an IL-10-dependent mechanism since 1,25(OH)(2)D(3)-treatment of IL-10-deficient macrophages failed to reproduce the characteristic repression on inflammatory mediators or T cell proliferation. Combined, these results highlight the possible therapeutic applicability of this natural immunomodulator, due to its ability to counteract macrophage inflammatory and T cell-activating pathways. PMID:22944250

Korf, Hannelie; Wenes, Mathias; Stijlemans, Benoit; Takiishi, Tatiana; Robert, Sofie; Miani, Michela; Eizirik, Decio L; Gysemans, Conny; Mathieu, Chantal

2012-12-01

258

Distinct Dendritic Cell Subsets Differentially Regulate the Class of Immune Response in vivo  

Microsoft Academic Search

Dendritic cells (DCs) are unique in their ability to stimulate T cells and initiate adaptive immunity. Injection of mice with the cytokine Flt3-ligand (FL) dramatically expands mature lymphoid and myeloid-related DC subsets. In contrast, injection of a polyethylene glycol-modified form of granulocyte\\/macrophage colony-stimulating factor (GM-CSF) into mice only expands the myeloid-related DC subset. These DC subsets differ in the cytokine

B. Pulendran; J. L. Smith; G. Caspary; K. Brasel; D. Pettit; E. Maraskovsky; C. R. Maliszewski

1999-01-01

259

B-cells and humoral immunity in multiple sclerosis. Implications for therapy  

Microsoft Academic Search

B-cells and humoral immunity have been implicated in the pathogenesis of multiple sclerosis. The most common pattern of demyelinating\\u000a pathology in multiple sclerosis is associated with the deposition of antibodies and the activation of complement, as well\\u000a as T-cells and macrophages. Plasmapheresis has been found to be an efficient therapeutic approach in patients with this type\\u000a of pathological lesion. Recent

Sangjin Oh; Cornelia Cudrici; Takahiro Ito; Horea Rus

2008-01-01

260

Alveolar type II epithelial cells produce interleukin-6 in vitro and in vivo. Regulation by alveolar macrophage secretory products.  

PubMed Central

The aims of this study were (a) to determine if rat alveolar type II (ATII) cells and human pulmonary epithelial-derived cells (A549 cell line) could generate IL-6 in vitro, (b) to characterize the cytokine regulation of IL-6 gene and protein expression in these cells, and (c) to detect the in vivo expression of immunoreactive IL-6 by human ATII cells. Rat ATII cells in primary culture secreted bioactive IL-6 and immunostained with an anti-IL-6 antiserum. Spontaneous IL-6 secretion by rat ATII cells amounted to 5,690 +/- 770 pg/ml/10(6) cells (n = 12) and was fivefold higher than spontaneous rat alveolar macrophages IL-6 secretion (1,052 +/- 286 pg/ml/10(6) cells, n = 8, P = 0.001). Rat alveolar macrophage conditioned media (CM) increased IL-6 secretion by rat ATII cells through the effect of IL-1 and TNF. IL-6 gene expression and IL-6 secretion by A549 cells was induced by IL-1 beta, TNF alpha, and by human alveolar macrophages and THP1 cells CM. Induction was abolished when CM were preincubated with anti-IL-1 beta and anti-TNF alpha antibody. The combination of IFN gamma and LPS induced the expression of IL-6 mRNA by A549 cells whereas LPS alone had no effect. Immunohistochemical staining evidenced the expression of immunoreactive IL-6 by hyperplastic ATII cells in fibrotic human lung, a condition in which alveolar macrophages are known to be activated. ATII cells in normal human lung did not express immunoreactive IL-6. Our findings demonstrate that ATII cells may be an important source of IL-6 in the alveolar space thereby participating to the regulation of the intra-alveolar immune response. Images PMID:8040328

Crestani, B; Cornillet, P; Dehoux, M; Rolland, C; Guenounou, M; Aubier, M

1994-01-01

261

The Majority of In Vitro Macrophage Activation Exhibited by Extracts of Some Immune Enhancing Botanicals is Due to Bacterial Lipoproteins and Lipopolysaccharides  

Technology Transfer Automated Retrieval System (TEKTRAN)

We have identified potent monocyte/macrophage activating bacterial lipoproteins within commonly used immune enhancing botanicals such as Echinacea, American ginseng and alfalfa sprouts. These bacterial lipoproteins, along with lipopolysaccharides, were substantially more potent than other bacteriall...

262

Playing hide-and-seek with host macrophages through the use of mycobacterial cell envelope phthiocerol dimycocerosates and phenolic glycolipids  

PubMed Central

Mycobacterial pathogens, including Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), have evolved a remarkable ability to evade the immune system in order to survive and to colonize the host. Among the most important evasion strategies is the capacity of these bacilli to parasitize host macrophages, since these are major effector cells against intracellular pathogens that can be used as long-term cellular reservoirs. Mycobacterial pathogens employ an array of virulence factors that manipulate macrophage function to survive and establish infection. Until recently, however, the role of mycobacterial cell envelope lipids as virulence factors in macrophage subversion has remained elusive. Here, we will address exclusively the proposed role for phthiocerol dimycocerosates (DIM) in the modulation of the resident macrophage response and that of phenolic glycolipids (PGL) in the regulation of the recruitment and phenotype of incoming macrophage precursors to the site of infection. We will provide a unique perspective of potential additional functions for these lipids, and highlight obstacles and opportunities to further understand their role in the pathogenesis of TB and other mycobacterial diseases. PMID:25538905

Arbues, Ainhoa; Lugo-Villarino, GeanCarlo; Neyrolles, Olivier; Guilhot, Christophe; Astarie-Dequeker, Catherine

2014-01-01

263

Direct cell-cell amplification and communication in immune system  

E-print Network

Direct cell-cell amplification and communication in immune system Direct cell-cell interactions cells of cell-cell recognition, as well as to a limited amount of activation stimul process has been that cytoskeleton plays a crucial role in signal amplification and perpetuation within a cell. Furthermore, contact

Shyamasundar, R.K.

264

Donor Immune Cells Attack Metastatic Breast Cancer  

Cancer.gov

In patients with metastatic breast cancer, immune cells from a genetically matched donor can attack and shrink tumors, researchers from the National Cancer Institute (NCI) announced today at the Annual Meeting of the American Society of Clinical Oncology in Chicago.

265

Immune Heterogeneity in Neuroinflammation: Dendritic Cells in the Brain  

PubMed Central

Dendritic cells (DC) are critical to an integrated immune response and serve as the key link between the innate and adaptive arms of the immune system. Under steady state conditions, brain DC’s act as sentinels, continually sampling their local environment. They share this function with macrophages derived from the same basic hemopoietic (bone marrow-derived) precursor and with parenchymal microglia that arise from a unique non-hemopoietic origin. While multiple cells may serve as antigen presenting cells (APCs), dendritic cells present both foreign and self-proteins to naïve T cells that, in turn, carry out effector functions that serve to protect or destroy. The resulting activation of the adaptive response is a critical step to resolution of injury or infection and is key to survival. In this review we will explore the critical roles that DCs play in the brain’s response to neuroinflammatory disease with emphasis on how the brain’s microenvironment impacts these actions. PMID:23114889

2014-01-01

266

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity  

PubMed Central

V?24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-? (mbTNF-?). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-?B signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15–transduced NKT cells. PMID:22565311

Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N.; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S.

2012-01-01

267

Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression  

Microsoft Academic Search

Macrophage migration inhibitory factor (MIF), which inhibits apoptosis and promotes angiogenesis, is expressed in cancers\\u000a suppressing immune surveillance. Its biological role in human glioblastoma is, however, only poorly understood. We examined\\u000a in-vivo expression of MIF in 166 gliomas and 23 normal control brains by immunohistochemistry. MIF immunoreactivity was enhanced\\u000a in neoplastic astrocytes in WHO grade II glioma and increased significantly

Michel Mittelbronn; Michael Platten; Pia Zeiner; Yvonne Dombrowski; Brigitte Frank; Cornelia Zachskorn; Patrick N. Harter; Michael Weller; Jörg Wischhusen

268

Heparin disaccharides inhibit tumor necrosis factor-alpha production by macrophages and arrest immune inflammation in rodents.  

PubMed

Inflammation is the clinical expression of chemical mediators such as the pro-inflammatory cytokine tumor necrosis factor (TNF-)-alpha produced by macrophages and other cells activated in the immune response. Hence, agents that can inhibit TNF-alpha may be useful in treating arthritis and other diseases resulting from uncontrolled inflammation. We now report that the cleavage of heparin by the enzyme heparinase I generates sulfated disaccharide (DS) molecules that can inhibit the production of TNF-alpha. Administration of nanogram amounts of the sulfated DS molecules to experimental animals inhibited delayed-type hypersensitivity to a skin sensitizer and arrested the joint swelling of immunologically induced adjuvant arthritis. Notably, the sulfated DS molecules showed a bell-shaped dose-response curve in vitro and in vivo: decreased effects were seen using amounts of the DS molecules higher than optimal. Thus, molecular regulators of inflammation can be released from the natural molecule heparin by the action of an enzyme. PMID:9352356

Cahalon, L; Lider, O; Schor, H; Avron, A; Gilat, D; Hershkoviz, R; Margalit, R; Eshel, A; Shoseyev, O; Cohen, I R

1997-10-01

269

Plague Bacteria Target Immune Cells During Infection  

Microsoft Academic Search

The plague is caused by the bacterium Yersinia pestis. Plague bacteria are thought to inject effector Yop proteins into host cells via the type III pathway. The identity of the host cells targeted for injection during plague infection is unknown. We found, using Yop beta-lactamase hybrids and fluorescent staining of live cells from plague-infected animals, that Y. pestis selected immune

Melanie M. Marketon; R. William DePaolo; Kristin L. DeBord; Bana Jabri; Olaf Schneewind

2005-01-01

270

Cell type-specific differences in ?-glucan recognition and signalling in porcine innate immune cells.  

PubMed

?-glucans exert receptor-mediated immunomodulating activities, including oxidative burst activity and cytokine secretion. The role of the ?-glucan receptors dectin-1 and complement receptor 3 (CR3) in the response of immune cells towards ?-glucans is still unresolved. Dectin-1 is considered as the main ?-glucan receptor in mice, while recent studies in man show that CR3 is more important in ?-glucan-mediated responses. This incited us to elucidate which receptor contributes to the response of innate immune cells towards particulate ?-glucans in pigs as the latter might serve as a better model for man. Our results show an important role of CR3 in ?-glucan recognition, as blocking this receptor strongly reduced the phagocytosis of ?-glucans and the ?-glucan-induced ROS production by porcine neutrophils. Conversely, dectin-1 does not seem to play a major role in ?-glucan recognition in neutrophils. However, recognition of ?-glucans appeared cell type-specific as both dectin-1 and CR3 are involved in the ?-glucan-mediated responses in pig macrophages. Moreover, CR3 signalling through focal adhesion kinase (FAK) was indispensable for ?-glucan-mediated ROS production and cytokine production in neutrophils and macrophages, while the Syk-dependent pathway was only partly involved in these responses. We may conclude that CR3 plays a cardinal role in ?-glucan signalling in porcine neutrophils, while macrophages use a more diverse receptor array to detect and respond towards ?-glucans. Nonetheless, FAK acts as a master switch that regulates ?-glucan-mediated responses in neutrophils as well as macrophages. PMID:25453580

Baert, Kim; Sonck, Eva; Goddeeris, Bruno M; Devriendt, Bert; Cox, Eric

2015-01-01

271

Identification of betaine as an osmolyte in rat liver macrophages (Kupffer cells)  

Microsoft Academic Search

BACKGROUND & AIMS: Anisosmotic cell volume changes were identified recently as a critical factor in the regulation of eicosanoid formation in stimulated liver macrophages (Kupffer cells). Therefore, the aim of this study was to investigate whether osmolytes are involved in the control of Kupffer cell function. METHODS: Cultured rat liver macrophages (Kupffer cells) were studied with respect to their functional

F Zhang; U Warskulat; M Wettstein; D Haussinger

1996-01-01

272

Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages  

Microsoft Academic Search

Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine norovirus 1 (MNV-1) infects macrophage-like cells in vivo and replicates in cultured primary dendritic cells and macrophages. MNV-1 growth was inhibited by the interferon-?? receptor and STAT-1, and was associated with extensive rearrangements of intracellular membranes. An amino acid substitution

Christiane E. Wobus; Stephanie M. Karst; Larissa B. Thackray; Kyeong-Ok Chang; Stanislav V. Sosnovtsev; Gaël Belliot; Anne Krug; Jason M. Mackenzie; Kim Y. Green; Herbert W. Virgin

2004-01-01

273

From mouth to macrophage: mechanisms of innate immune subversion by Mycobacterium avium subsp. paratuberculosis  

PubMed Central

Johne’s disease (JD) is a chronic enteric infection of cattle caused by Mycobacterium avium subsp. paratuberculosis (MAP). The high economic cost and potential zoonotic threat of JD have driven efforts to develop tools and approaches to effectively manage this disease within livestock herds. Efforts to control JD through traditional animal management practices are complicated by MAP’s ability to cause long-term environmental contamination as well as difficulties associated with diagnosis of JD in the pre-clinical stages. As such, there is particular emphasis on the development of an effective vaccine. This is a daunting challenge, in large part due to MAP’s ability to subvert protective host immune responses. Accordingly, there is a priority to understand MAP’s interaction with the bovine host: this may inform rational targets and approaches for therapeutic intervention. Here we review the early host defenses encountered by MAP and the strategies employed by the pathogen to avert or subvert these responses, during the critical period between ingestion and the establishment of persistent infection in macrophages. PMID:24885748

2014-01-01

274

Diet Modifies the Neuroimmune System by Influencing Macrophage Activation  

ERIC Educational Resources Information Center

It has long been appreciated that adequate nutrition is required for proper immune function and it is now recognized that dietary components contribute to modulation of immune cells, subsequently impacting the whole body's response during an immune challenge. Macrophage activation plays a critical role in the immune system and directs the…

Sherry, Christina Lynn

2009-01-01

275

Innate Immune Response of Alveolar Macrophage to House Dust Mite Allergen Is Mediated through TLR2/-4 Co-Activation  

PubMed Central

House dust mite, Dermatophagoides pteronyssinus (Der p), is one of the major allergens responsible for allergic asthma. However, the putative receptors involved in the signalization of Der p to the innate immune cells are still poorly defined as well as the impact of their activation on the outcome of the allergen-induced cell response. We previously reported that the HDM activation of mouse alveolar macrophages (AM) involves the TLR4/CD14 cell surface receptor complex. Here using a TLR ligand screening essay, we demonstrate that HDM protein extract engages the TLR2, in addition to the TLR4, in engineered TLR-transfected HEK cells but also in the MH-S mouse alveolar macrophage cell line model. Moreover we found that the concomitant recruitment of the MH-S cell’s TLR2 and TLR4 receptors by the HDM extract activates the MyD88-dependent signaling pathway and leads to the secretion of the NF-?B regulated pro-inflammatory factors NO and TNF-?. However unlike with the canonical TLR4 ligand (i.e. the bacterial LPS) mobilization of TLR4 by the HDM extract induces a reduced production of the IL-12 pro-inflammatory cytokine and fails to trigger the expression of the T-bet transcription factor. Finally we demonstrated that HDM extract down-regulates LPS induced IL-12 and T-bet expression through a TLR2 dependent mechanism. Therefore, we propose that the simultaneous engagement of the TLR2 and TLR4 receptors by the HDM extract results in a cross regulated original activation pattern of the AM which may contribute to the Th2 polarization of the allergen-induced immune response. The deciphering of these cross-regulation networks is of prime importance to open the way for original therapeutic strategies taking advantage of these receptors and their associated signaling pathways to treat allergic asthma. PMID:24098413

Liu, Chia-Fang; Drocourt, Daniel; Puzo, Germain; Wang, Jiu-Yao; Riviere, Michel

2013-01-01

276

Accessory cells in the immune defense of the dental pulp.  

PubMed

This communication focuses on the participation of accessory cells in the initial recognition and processing of antigenic substances in the dental pulp. Immunohistochemical analyses have demonstrated the presence of two types of accessory cells--one with a dendritic morphology located in the periphery of the pulp and one with a macrophage-like appearance located more centrally. Functional studies in vitro have provided evidence for the dendritic cells being the most significant of the two cells regarding their capacity to induce T-cell proliferation. Studies on ontogeny have revealed that the appearance of pulp accessory cells is delayed compared to other peripheral tissues. In experimentally induced pulp lesions a rapid increase of cells with morphologic and phenotypic features similar to normally occurring accessory cells was found. These data demonstrate that the dental pulp contains the necessary cellular constituents to mount an immunologic defense reaction. Future studies should focus on elucidating possible interactions between these immune cells and the neurovascular system of the pulp. PMID:1508890

Jontell, M; Bergenholtz, G

1992-01-01

277

Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma.  

PubMed

Although malignant cells can be recognized and controlled by the immune system, in patients with clinically apparent cancer immunosurveillance has failed. To better understand local immunoregulatory processes that impact on cancer progression, we correlated intratumoral immunological profiles with the survival of patients affected by primary clear cell renal cell carcinoma (ccRCC). A retrospective analysis of 54 primary ccRCC samples for 31 different immune response-related transcripts, revealed a negative correlation of CD68 (a marker of tumor-associated macrophages, TAMs) and FOXP3 (a marker of regulatory T cells, Tregs) with survival. The subsequent analysis of 12 TAM-related transcripts revealed an association between the genes coding for CD163, interferon regulatory factor 4 (IRF4) and fibronectin 1 (FN1), all of which have been linked to the M2 TAM phenotype, with reduced survival and increased tumor stage, whereas the opposite was the case for the M1-associated gene coding for inducible nitric oxide synthetase (iNOS). The M2 signature of (CD68(+)) TAMs was found to correlate with CD163 expression, as determined in prospectively collected fresh ccRCC tissue samples. Upon co-culture with autologous tumor cells, CD11b(+) cells isolated from paired blood samples expressed CD163 and other M2-associated proteins, suggesting that the malignant cells promote the accumulation of M2 TAMs. Furthermore, the tumor-associated milieu as well as isolated TAMs induced the skewing of autologous, blood-derived CD4(+) T cells toward a more immunosuppressive phenotype, as shown by decreased production of effector cytokines, increased production of interleukin-10 (IL-10) and enhanced expression of the co-inhibitory molecules programmed death 1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3). Taken together, our data suggest that ccRCC progressively attracts macrophages and induces their skewing into M2 TAMs, in turn subverting tumor-infiltrating T cells such that immunoregulatory functions are increased at the expense of effector functions. PMID:23687622

Dannenmann, Stefanie Regine; Thielicke, Julia; Stöckli, Martina; Matter, Claudia; von Boehmer, Lotta; Cecconi, Virginia; Hermanns, Thomas; Hefermehl, Lukas; Schraml, Peter; Moch, Holger; Knuth, Alexander; van den Broek, Maries

2013-03-01

278

Suppressive effect on activation of macrophages by Lactobacillus casei strain Shirota genes determining the synthesis of cell wall-associated polysaccharides.  

PubMed

Although many Lactobacillus strains used as probiotics are believed to modulate host immune responses, the molecular natures of the components of such probiotic microorganisms directly involved in immune modulation process are largely unknown. We aimed to assess the function of polysaccharide moiety of the cell wall of Lactobacillus casei strain Shirota as a possible immune modulator which regulates cytokine production by macrophages. A gene survey of the genome sequence of L. casei Shirota hunted down a unique cluster of 10 genes, most of whose predicted amino acid sequences had similarities to various extents to known proteins involved in biosynthesis of extracellular or capsular polysaccharides from other lactic acid bacteria. Gene knockout mutants of eight genes from this cluster resulted in the loss of reactivity to L. casei Shirota-specific monoclonal antibody and extreme reduction of high-molecular-mass polysaccharides in the cell wall fraction, indicating that at least these genes are involved in biosynthesis of high-molecular-mass cell wall polysaccharides. By adding heat-killed mutant cells to mouse macrophage cell lines or to mouse spleen cells, the production of tumor necrosis factor alpha, interleukin-12 (IL-12), IL-10, and IL-6 was more stimulated than by wild-type cells. In addition, these mutants additively enhanced lipopolysaccharide-induced IL-6 production by RAW 264.7 mouse macrophage-like cells, while wild-type cells significantly suppressed the IL-6 production of RAW 264.7. Collectively, these results indicate that this cluster of genes of L. casei Shirota, which have been named cps1A, cps1B, cps1C, cps1D, cps1E, cps1F, cps1G, and cps1J, determine the synthesis of the high-molecular-mass polysaccharide moiety of the L. casei Shirota cell wall and that this polysaccharide moiety is the relevant immune modulator which may function to reduce excessive immune reactions during the activation of macrophages by L. casei Shirota. PMID:18552190

Yasuda, Emi; Serata, Masaki; Sako, Tomoyuki

2008-08-01

279

Development and function of human innate immune cells in a humanized mouse model  

PubMed Central

Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models are unable to support development of human innate immune cells, including myeloid cells and NK cells. Here we describe a mouse strain, called MI(S)TRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked in to their respective mouse loci. The human cytokines support the development and function of monocytes/macrophages and natural killer cells derived from human fetal liver or adult CD34+ progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MI(S)TRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology. PMID:24633240

Rongvaux, Anthony; Willinger, Tim; Martinek, Jan; Strowig, Till; Gearty, Sofia V.; Teichmann, Lino L.; Saito, Yasuyuki; Marches, Florentina; Halene, Stephanie; Palucka, A. Karolina; Manz, Markus G.; Flavell, Richard A.

2014-01-01

280

Tetherin Can Restrict Cell-Free and Cell-Cell Transmission of HIV from Primary Macrophages to T Cells  

PubMed Central

Bst-2/Tetherin inhibits the release of HIV by tethering newly formed virus particles to the plasma membrane of infected cells. Although the mechanisms of Tetherin-mediated restriction are increasingly well understood, the biological relevance of this restriction in the natural target cells of HIV is unclear. Moreover, whether Tetherin exerts any restriction on the direct cell-cell spread of HIV across intercellular contacts remains controversial. Here we analyse the restriction endogenous Tetherin imposes on HIV transmission from primary human macrophages, one of the main targets of HIV in vivo. We find that the mRNA and protein levels of Tetherin in macrophages are comparable to those in T cells from the same donors, and are highly upregulated by type I interferons. Improved immunocytochemistry protocols enable us to demonstrate that Tetherin localises to the cell surface, the trans-Golgi network, and the macrophage HIV assembly compartments. Tetherin retains budded virions in the assembly compartments, thereby impeding the release and cell-free spread of HIV, but it is not required for the maintenance of these compartments per se. Notably, using a novel assay to quantify cell-cell spread, we show that Tetherin promotes the transfer of virus clusters from macrophages to T cells and thereby restricts the direct transmission of a dual-tropic HIV-1. Kinetic analyses provide support for the notion that this direct macrophage-T cell spread is mediated, at least in part, by so-called virological synapses. Finally, we demonstrate that the viral Vpu protein efficiently downregulates the cell surface and overall levels of Tetherin, and thereby abrogates this HIV restriction in macrophages. Together, our study shows that Tetherin, one of the most potent HIV restriction factors identified to date, can inhibit virus spread from primary macrophages, regardless of the mode of transmission. PMID:24991932

Giese, Sebastian; Marsh, Mark

2014-01-01

281

Antitumor immune responses mediated by dendritic cells  

PubMed Central

Dendritic cells (DCs) are essential for the induction of adaptive immune responses against malignant cells by virtue of their capacity to effectively cross-present exogenous antigens to T lymphocytes. Dying cancer cells are indeed a rich source of antigens that may be harnessed for the development of DC-based vaccines. In particular, malignant cells succumbing to apoptosis, rather than necrosis, appear to release antigens in a manner that allows for the elicitation of adaptive immune responses. In this review, we describe the processes that mediate the cross-presentation of antigens released by apoptotic cancer cells to CD8+ T lymphocytes, resulting in the activation of protective tumor-specific immune responses. PMID:24482744

Spel, Lotte; Boelens, Jaap-Jan; Nierkens, Stefan; Boes, Marianne

2013-01-01

282

Selective colorectal cancer cell lysates enhance the immune function of mature dendritic cells in vitro.  

PubMed

The aim of the present study was to determine the most effective antigen with which to mature dendritic cells (DCs). The immune function of DCs loaded with lysates from three different colorectal cancer cell lines was compared. DCs were induced using granulocyte macrophage colony?stimulating factor, interleukin (IL)?4 and tumor necrosis factor-? from the peripheral blood mononuclear cells of patients with colorectal cancer, and loaded with lysates from Colo320, SW480 and SW620 colorectal cancer cell lines, respectively. Autogenous T cells were co?cultured with mature DCs. Surface markers and the secretory function of mature DCs and stimulated T cells were then analyzed. MTT assays were used to evaluate the killing capacity of autogenous cytotoxic T lymphocytes (CTLs). Compared with control, cluster of differentiation (CD)1a, CD83 and CD86, and human leukocyte antigen?DR expression levels were significantly higher in DCs matured using cancer cell lysates. In addition, IL?12 secretion levels were elevated. Autogenous T cells stimulated with DCs that were matured using cancer cell lysates showed a higher proliferation capacity, increased interferon-? secretion levels and stronger cytotoxic abilities compared with control cells. Among the three cell lines, SW480 lysates were most effective at promoting DC and T cell function. The results showed that SW480 lysates are more efficient than Colo320 and SW620 lysates in inducing DC immune function and activating the antitumor function of autogenous T cells. PMID:25394863

Chen, Lihong; Meng, Du; Zhao, Lei; Liu, Rui; Bai, Peisong; Wang, Le; Xiao, Juxiang

2015-03-01

283

Soluble factors from colonic epithelial cells contribute to gut homeostasis by modulating macrophage phenotype.  

PubMed

Intestinal macrophages originate from inflammatory blood monocytes which migrate to the intestine, where they differentiate into anti-inflammatory macrophages through a number of transitional stages. These macrophages typically remain hypo-responsive to commensal bacteria and food Ags in the intestine, yet also retain the ability to react to invading pathogens. In this study we examined the role of epithelial cells in inducing this intestinal macrophage phenotype. Using an in vitro system we showed that, in two-dimensional culture, epithelial cell-derived factors from a murine cell line, CMT-93, are sufficient to induce phenotypic changes in macrophages. Exposure of monocyte-derived macrophages, J774A.1, to soluble factors derived from epithelial cells, induced an altered phenotype similar to that of intestinal macrophages with decreased production of IL-12p40, IL-6 and IL-23 and expression of MHC ?? and CD80 following TLR ligation. Furthermore, these conditioned macrophages showed enhanced phagocytic activity in parallel with low respiratory burst and NO production, similar to the response seen in intestinal macrophages. Our findings suggest a role for colonic epithelial cells in modulation of macrophage phenotype for maintenance of gut homeostasis. Further understanding of the cell interactions that maintain homeostasis in the gut could reveal novel therapeutic strategies to restore the balance in disease. PMID:25298104

Kristek, Maja; Collins, Laura E; DeCourcey, Joseph; McEvoy, Fiona A; Loscher, Christine E

2014-10-01

284

Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches  

SciTech Connect

The ability of macrophages to promote vascular growth has been associated with the secretion and local delivery of classic proangiogenic factors (e.g., VEGF-A and proteases). More recently, a series of studies have also revealed that physical contact of macrophages with growing blood vessels coordinates vascular fusion of emerging sprouts. Interestingly, the interactions between macrophages and vascular endothelial cells (ECs) appear to be bidirectional, such that activated ECs also support the expansion and differentiation of proangiogenic macrophages from myeloid progenitors. Here, we discuss recent findings suggesting that dynamic angiogenic vascular niches might also exist in vivo, e.g. in tumors, where sprouting blood vessels and immature myeloid cells like monocytes engage in heterotypic interactions that are required for angiogenesis. Finally, we provide an account of emerging mechanisms of cell-to-cell communication that rely on secreted microvesicles, such as exosomes, which can offer a vehicle for the rapid exchange of molecules and genetic information between macrophages and ECs engaged in angiogenesis. -- Highlights: • Macrophages promote angiogenesis by secreting proangiogenic factors. • Macrophages modulate angiogenesis via cell-to-cell contacts with endothelial cells. • Endothelial cells promote the differentiation of proangiogenic macrophages. • Macrophages and endothelial cells may cooperate to form angiogenic vascular niches.

Baer, Caroline; Squadrito, Mario Leonardo [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Iruela-Arispe, M. Luisa, E-mail: arispe@mcdb.ucla.edu [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Department of Molecular, Cell and Developmental Biology and Molecular Biology Institute, University of California, Los Angeles 90095, CA (United States); De Palma, Michele, E-mail: michele.depalma@epfl.ch [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland)

2013-07-01

285

Experimental Chagas disease. Innate immune response in Balb/c mice previously vaccinated with Trypanosoma rangeli. I. The macrophage shows immunological memory: Reality or fiction?  

PubMed

Chagas' disease, caused by Trypanosoma cruzi, is a major vector borne health problem in Latin America and an emerging or re-emerging infectious disease in several countries. Immune response to T. cruzi infection is highly complex and involves many components, both regulators and effectors. Although different parasites have been shown to activate different mechanisms of innate immunity, T. cruzi is often able to survive and replicate in its host because they are well adapted to resisting host defences. An experimental model for vaccinating mice with Trypanosoma rangeli, a parasite closely related to T. cruzi, but nonpathogenic to humans, has been designed in our laboratory, showing protection against challenge with T. cruzi infection. The aim of this work was to analyze some mechanisms of the early innate immune response in T. rangeli vaccinated mice challenged with T. cruzi. For this purpose, some interactions were studied between T. cruzi and peritoneal macrophages of mice vaccinated with T. rangeli, infected or not with T. cruzi and the levels of some molecules or soluble mediators which could modify these interactions. The results in vaccinated animals showed a strong innate immune response, where the adherent cells of the vaccinated mice revealed important phagocytic activity, and some soluble mediator (Respiratory Burst: significantly increase, p ? 0.03; NO: the levels of vaccinated animals were lower than those of the control group; Arginasa: significantly increase, p ? 0.04). The results showed an important role in the early elimination of the parasites and their close relation with the absence of histological lesions that these animals present with regard to the only infected mice. This behaviour reveals that the macrophages act with some type of memory, recognizing the antigens to which they have previously been exposed, in mice were vaccinated with T. rangeli, which shares epitopes with T. cruzi. PMID:24321621

Basso, B; Marini, V

2014-04-01

286

Cells of the synovium in rheumatoid arthritis. Macrophages  

Microsoft Academic Search

The multitude and abundance of macrophage-derived mediators in rheumatoid arthritis and their paracrine\\/autocrine effects identify macrophages as local and systemic amplifiers of disease. Although uncovering the etiology of rheumatoid arthritis remains the ultimate means to silence the pathogenetic process, efforts in understanding how activated macrophages influence disease have led to optimization strategies to selectively target macrophages by agents tailored to

Raimund W Kinne; Bruno Stuhlmüller; Gerd-R Burmester

2007-01-01

287

The Process of Macrophage Migration Promotes Matrix Metalloproteinase-Independent Invasion by Tumor Cells  

PubMed Central

Tumor-associated macrophages are known to amplify the malignant potential of tumors by secreting a variety of cytokines and proteases involved in tumor cell invasion and metastasis, but how these macrophages infiltrate tumors and whether the macrophage migration process facilitates tumor cell invasion remain poorly documented. To address these questions, we used cell spheroids of breast carcinoma SUM159PT cells as an in vitro model of solid tumors. We found that macrophages used both the mesenchymal mode requiring matrix metalloproteinases (MMPs) and the amoeboid migration mode to infiltrate tumor cell spheroids. Whereas individual SUM159PT cells invaded Matrigel using an MMP-dependent mesenchymal mode, when they were grown as spheroids, tumor cells were unable to invade the Matrigel surrounding spheroids. When spheroids were infiltrated or in contact with macrophages, tumor cell invasiveness was restored. It was dependent on the capacity of macrophages to remodel the matrix and migrate in an MMP-independent mesenchymal mode. This effect of macrophages was much reduced when spheroids were infiltrated by Matrigel migration-defective Hck?/? macrophages. In the presence of macrophages, SUM159PT migrated into Matrigel in the proximity of macrophages and switched from an MMP-dependent mesenchymal migration to an amoeboid mode resistant to protease inhibitors. Thus, in addition to the well-described paracrine loop between macrophages and tumor cells, macrophages can also contribute to the invasiveness of tumor cells by remodeling the extracellular matrix and by opening the way to exit the tumor and colonize the surrounding tissues in an MMP-dispensable manner. PMID:21880978

Guiet, Romain; Van Goethem, Emeline; Cougoule, Céline; Balor, Stéphanie; Valette, Annie; Saati, Talal Al; Lowell, Clifford A.; Le Cabec, Véronique; Maridonneau-Parini, Isabelle

2014-01-01

288

In Vitro Interactions between Bacteria, Osteoblast-Like Cells and Macrophages in the Pathogenesis of Biomaterial-Associated Infections  

PubMed Central

Biomaterial-associated infections constitute a major clinical problem that is difficult to treat and often necessitates implant replacement. Pathogens can be introduced on an implant surface during surgery and compete with host cells attempting to integrate the implant. The fate of a biomaterial implant depends on the outcome of this race for the surface. Here we studied the competition between different bacterial strains and human U2OS osteoblast-like cells (ATCC HTB-94) for a poly(methylmethacrylate) surface in the absence or presence of macrophages in vitro using a peri-operative contamination model. Bacteria were seeded on the surface at a shear rate of 11 1/s prior to adhesion of U2OS cells and macrophages. Next, bacteria, U2OS cells and macrophages were allowed to grow simultaneously under low shear conditions (0.14 1/s). The outcome of the competition between bacteria and U2OS cells for the surface critically depended on bacterial virulence. In absence of macrophages, highly virulent Staphylococcus aureus or Pseudomonas aeruginosa stimulated U2OS cell death within 18 h of simultaneous growth on a surface. Moreover, these strains also caused cell death despite phagocytosis of adhering bacteria in presence of murine macrophages. Thus U2OS cells are bound to loose the race for a biomaterial surface against S. aureus or P. aeruginosa, even in presence of macrophages. In contrast, low-virulent Staphylococcus epidermidis did not cause U2OS cell death even after 48 h, regardless of the absence or presence of macrophages. Clinically, S. aureus and P. aeruginosa are known to yield acute and severe biomaterial-associated infections in contrast to S. epidermidis, mostly known to cause more low-grade infection. Thus it can be concluded that the model described possesses features concurring with clinical observations and therewith has potential for further studies on the simultaneous competition for an implant surface between tissue cells and pathogenic bacteria in presence of immune system components. PMID:21931858

Subbiahdoss, Guruprakash; Saldarriaga Fernández, Isabel C.; da Silva Domingues, Joana F.; Kuijer, Roel; van der Mei, Henny C.; Busscher, Henk J.

2011-01-01

289

Uranyl nitrate-exposed rat alveolar macrophages cell death: influence of superoxide anion and TNF ? mediators.  

PubMed

Uranium compounds are widely used in the nuclear fuel cycle, military and many other diverse industrial processes. Health risks associated with uranium exposure include nephrotoxicity, cancer, respiratory, and immune disorders. Macrophages present in body tissues are the main cell type involved in the internalization of uranium particles. To better understand the pathological effects associated with depleted uranium (DU) inhalation, we examined the metabolic activity, phagocytosis, genotoxicity and inflammation on DU-exposed rat alveolar macrophages (12.5-200 ?M). Stability and dissolution of DU could differ depending on the dissolvent and in turn alter its biological action. We dissolved DU in sodium bicarbonate (NaHCO? 100 mM) and in what we consider a more physiological vehicle resembling human internal media: sodium chloride (NaCl 0.9%). We demonstrate that uranyl nitrate in NaCl solubilizes, enters the cell, and elicits its cytotoxic effect similarly to when it is diluted in NaHCO?. We show that irrespective of the dissolvent employed, uranyl nitrate impairs cell metabolism, and at low doses induces both phagocytosis and generation of superoxide anion (O??). At high doses it provokes the secretion of TNF? and through all the range of doses tested, apoptosis. We herein suggest that at DU low doses O?? may act as the principal mediator of DNA damage while at higher doses the signaling pathway mediated by O?? may be blocked, prevailing damage to DNA by the TNF? route. The study of macrophage functions after uranyl nitrate treatment could provide insights into the pathophysiology of uranium-related diseases. PMID:22561334

Orona, N S; Tasat, D R

2012-06-15

290

Global Transcriptome Analysis of Staphylococcus aureus Biofilms in Response to Innate Immune Cells  

PubMed Central

The potent phagocytic and microbicidal activities of neutrophils and macrophages are among the first lines of defense against bacterial infections. Yet Staphylococcus aureus is often resistant to innate immune defense mechanisms, especially when organized as a biofilm. To investigate how S. aureus biofilms respond to macrophages and neutrophils, gene expression patterns were profiled using Affymetrix microarrays. The addition of macrophages to S. aureus static biofilms led to a global suppression of the biofilm transcriptome with a wide variety of genes downregulated. Notably, genes involved in metabolism, cell wall synthesis/structure, and transcription/translation/replication were among the most highly downregulated, which was most dramatic at 1 h compared to 24 h following macrophage addition to biofilms. Unexpectedly, few genes were enhanced in biofilms after macrophage challenge. Unlike coculture with macrophages, coculture of S. aureus static biofilms with neutrophils did not greatly influence the biofilm transcriptome. Collectively, these experiments demonstrate that S. aureus biofilms differentially modify their gene expression patterns depending on the leukocyte subset encountered. PMID:24042108

Scherr, Tyler D.; Roux, Christelle M.; Hanke, Mark L.; Angle, Amanda; Dunman, Paul M.

2013-01-01

291

Cell Host & Microbe Leishmania Evades Host Immunity  

E-print Network

Cell Host & Microbe Article Leishmania Evades Host Immunity by Inhibiting Antigen Cross cells engulf microorganisms at sites of infection, leads to the formation of phagosomes, where microbes of the microbicidal properties required for the killing of microbes (Desjardins et al., 2005; Jutras and Desjardins

Arnold, Jonathan

292

Regulatory T cells in cutaneous immune responses  

Microsoft Academic Search

Regulatory T cells (Treg) are a subset of T cells with strong immunosuppressive activity. In the skin, it has recently been revealed that Treg play important roles not only in the maintenance of skin homeostasis but also in the regulation of the immune responses, such as contact hypersensitivity and atopic dermatitis. Furthermore, the skin plays important roles in the induction

Tetsuya Honda; Yoshiki Miyachi; Kenji Kabashima

2011-01-01

293

Enterococcus faecalis infection activates phosphatidylinositol 3-kinase signaling to block apoptotic cell death in macrophages.  

PubMed

Apoptosis is an intrinsic immune defense mechanism in the host response to microbial infection. Not surprisingly, many pathogens have evolved various strategies to manipulate this important pathway to benefit their own survival and dissemination in the host during infection. To our knowledge, no attempts have been made to explore the host cell survival signals modulated by the bacterium Enterococcus faecalis. Here, we show for the first time that during early stages of infection, internalized enterococci can prevent host cell (RAW264.7 cells, primary macrophages, and mouse embryonic fibroblasts [MEFs]) apoptosis induced by a wide spectrum of proapoptotic stimuli. Activation of caspase 3 and cleavage of the caspase 3 substrate poly(ADP-ribose) polymerase were inhibited in E. faecalis-infected cells, indicating that E. faecalis protects macrophages from apoptosis by inhibiting caspase 3 activation. This antiapoptotic activity in E. faecalis-infected cells was dependent on the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which resulted in the increased expression of the antiapoptotic factor Bcl-2 and decreased expression of the proapoptotic factor Bax. Further analysis revealed that active E. faecalis physiology was important for inhibition of host cell apoptosis, and this feature seemed to be a strain-independent trait among E. faecalis isolates. Employing a mouse peritonitis model, we also determined that cells collected from the peritoneal lavage fluid of E. faecalis-infected mice showed reduced levels of apoptosis compared to cells from uninfected mice. These results show early modulation of apoptosis during infection and have important implications for enterococcal pathogenesis. PMID:25267834

Zou, Jun; Shankar, Nathan

2014-12-01

294

Effects of Orthopaedic Polymer Particles on Chemotaxis of Macrophages and Mesenchymal Stem Cells  

PubMed Central

Wear particles generated from total joint arthroplasty (TJA) stimulate macrophages to release chemokines. The role of chemokines released from wear particle-stimulated macrophages on the migration of macrophages and osteoprogenitor cells in vitro has not been elucidated. In this study, we challenged murine macrophages (RAW 264.7) with clinically relevant polymethyl methacrylate (PMMA, 1-10 ?m) and ultra high molecular weight polyethylene (UHMWPE, 2-3 ?m) particles. The chemotactic effects of the conditioned media (CM) were tested in vitro using human macrophages (THP-1) and human mesenchymal stem cells (MSCs) as the migrating cells. CM collected from both particle types had a chemotactic effect on human macrophages, which could be eliminated by monocyte chemotactic protein-1 (MCP-1) neutralizing antibody. Blocking the CCR1 receptor eliminated the chemotactic effect, while CCR2 antibody only partially decreased THP-1 cell migration. CM from PMMA but not UHMWPE-exposed macrophages led to chemotaxis of MSCs; this effect could be eliminated by macrophage inflammatory protein-1 alpha (MIP-1?) neutralizing antibody. Neither CCR1 nor CCR2 blocking antibodies showed an effect on the migration of MSCs. Chemokines released by macrophages stimulated by wear particles can have an effect on the migration of macrophages and MSCs. This effect seems to be dependent on the particle type, and may be modulated by MCP-1 and MIP-1?, however more than one chemokine may be necessary for chemotaxis. PMID:20694994

Huang, Zhinong; Ma, Ting; Ren, Pei-Gen; Smith, R. Lane; Goodman, Stuart B

2010-01-01

295

The linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) regulates triggering receptor expressed on myeloid cells (TREM)-2 signaling and macrophage inflammatory responses independently of the linker for activation of T cells.  

PubMed

Triggering receptor expressed on myeloid cells-2 (TREM-2) is rapidly emerging as a key regulator of the innate immune response via its regulation of macrophage inflammatory responses. Here we demonstrate that proximal TREM-2 signaling parallels other DAP12-based receptor systems in its use of Syk and Src-family kinases. However, we find that the linker for activation of T cells (LAT) is severely reduced as monocytes differentiate into macrophages and that TREM-2 exclusively uses the linker for activation of B cells (LAB encoded by the gene Lat2(-/-)) to mediate downstream signaling. LAB is required for TREM-2-mediated activation of Erk1/2 and dampens proximal TREM-2 signals through a novel LAT-independent mechanism resulting in macrophages with proinflammatory properties. Thus, Lat2(-/-) macrophages have increased TREM-2-induced proximal phosphorylation, and lipopolysaccharide stimulation of these cells leads to increased interleukin-10 (IL-10) and decreased IL-12p40 production relative to wild type cells. Together these data identify LAB as a critical, LAT-independent regulator of TREM-2 signaling and macrophage development capable of controlling subsequent inflammatory responses. PMID:19948717

Whittaker, Gillian C; Orr, Selinda J; Quigley, Laura; Hughes, Laurel; Francischetti, Ivo M B; Zhang, Weigou; McVicar, Daniel W

2010-01-29

296

Analysis of immune cells within the healthy oral mucosa of specific pathogen-free cats.  

PubMed

The oral mucosa is an important interface for host-environment interactions. Based on previous studies, it is generally accepted that the cellular compartments of the oral immune system comprise organized mucosal-associated lymphoid tissues as well as diffusely and focally distributed T- and to lesser extent B-lymphocytes, oral mucosal Langerhans cells (OMLC), macrophages and mast cells. However, a comprehensive quantification of the cellular elements in the oral mucous membranes of the cat has not been reported. The aim of this study was to provide a comprehensive analysis of the immune cell compartments in the oral mucous membranes and anatomically related tissues of healthy cats. Multiple biopsies of the oral mucous membranes and related tissues were obtained from four specific pathogen-free cats for histological and immunohistochemical assessment of lymphocyte subsets, OMLC, macrophages and mast cells. T-lymphocyte subsets, OMLC, mast cells and macrophages were present in varying frequencies among the tissue compartments of the feline oral cavity. B-lymphocytes were not identified in any of the examined tissues except the tonsils and mandibular lymph nodes. Lymphocytic aggregates (follicles) were found in the palatoglossal folds and the gingiva. We describe the topographical distribution of various leucocyte subsets in the normal healthy feline oral mucosa, and demonstrate regional differences in the distribution of these cells. PMID:20809918

Arzi, B; Murphy, B; Baumgarth, N; Vapniarsky, N; Nemec, A; Naydan, D K; Cox, D P; Verstraete, F J M

2011-02-01

297

An adenoviral vector for probing promoter activity in primary immune cells  

PubMed Central

Functional analysis of the DNA regulatory regions that control gene expression has largely been performed through transient transfection of promoter–reporter constructs into transformed cells. However, transformed cells are often poor models of primary cells. To directly analyze DNA regulatory regions in primary cells, we generated a novel adenoviral luciferase reporter vector, pShuttle-luciferase-GFP (pSLUG) that contains a promoterless luciferase cassette (with an upstream cloning site) for probing promoter activity, and a GFP expression cassette that allows for the identification of transduced cells. Recombinant adenoviruses generated from this vector can transduce a wide range of primary immune cells with high efficiency, including human macrophages, dendritic cells and T cells; and mouse T cells transgenic for the coxsackie and adenoviral receptor (CAR). In primary T cells, we show inducible nuclear factor of activated T cells (NF-AT) activity using a recombinant pSLUG adenovirus containing a consensus NF-AT promoter. We further show inducible IL-12/23 p40 promoter activity in primary macrophages and dendritic cells using a recombinant pSLUG adenovirus containing the proximal human IL-12/23 p40 promoter. The pSLUG system promises to be a powerful tool for the analysis of DNA regulatory regions in diverse types of primary immune cells. PMID:16563424

Tripathi, Pulak; Madan, Rajat; Chougnet, Claire; Divanovic, Senad; Ma, Xiaojing; Wahl, Larry M.; Gajewski, Thomas; Karp, Christopher L.; Hildeman, David A.

2010-01-01

298

Activated Human Mast Cells Induce LOX-1-Specific Scavenger Receptor Expression in Human Monocyte-Derived Macrophages  

PubMed Central

Objective Activated mast cells in atherosclerotic lesions degranulate and release bioactive compounds capable of regulating atherogenesis. Here we examined the ability of activated human primary mast cells to regulate the expression of the major scavenger receptors in cultured human primary monocyte-derived macrophages (HMDMs). Results Components released by immunologically activated human primary mast cells induced a transient expression of lectin-like oxidized LDL receptor (LOX-1) mRNA in HMDMs, while the expression of two other scavenger receptors, MSR1 and CD36, remained unaffected. The LOX-1-inducing secretory components were identified as histamine, tumor necrosis factor alpha (TNF-?), and transforming growth factor beta (TGF-?1), which exhibited a synergistic effect on LOX-1 mRNA expression. Histamine induced a transient expression of LOX-1 protein. Mast cell –induced increase in LOX-1 expression was not associated with increased uptake of oxidized LDL by the macrophages. Conclusions Mast cell-derived histamine, TNF-?, and TGF-?1 act in concert to induce a transient increase in LOX-1 expression in human primary monocyte-derived macrophages. The LOX-1-inducing activity potentially endows mast cells a hitherto unrecognized role in the regulation of innate immune reactions in atherogenesis. PMID:25250731

Alanne-Kinnunen, Mervi; Lappalainen, Jani; Öörni, Katariina; Kovanen, Petri T.

2014-01-01

299

The role of macrophage chemoattractant signaling in cancer cell migration, metastasis and neovascularization  

E-print Network

work on profiling gene expression in our macrophage and cancer cells.work synergistically to potentiate the chemotaxis of CT26 colon cancer cells.work has demonstrated an important role for SDF-1? in mediating colon cancer cell

Liu, Tiffany

2010-01-01

300

Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells.  

PubMed

The coagulopathy of acute promyelocytic leukemia (APL) is mainly related to procoagulant substances and fibrinolytic activators of APL blasts, but the fate of these leukemic cells is unknown. The aim of this study was to investigate the removal of APL blasts by macrophages and endothelial cells in vitro and consequent procoagulant and fibrinolytic activity of APL cells. We found that human umbilical vein endothelial cells as well as THP-1 and monocyte-derived macrophages bound, engulfed, and subsequently degraded immortalized APL cell line NB4 and primary APL cells. Lactadherin promoted phagocytosis of APL cells in a time-dependent fashion. Furthermore, factor Xa and prothrombinase activity of phosphatidylserine-exposed target APL cells was time-dependently decreased after incubation with phagocytes (THP-1-derived macrophages or HUVECs). Thrombin production on target APL cells was reduced by 40%-45% after 2 hours of coincubation with phagocytes and 80% by a combination of lactadherin and phagocytes. Moreover, plasmin generation of target APL cells was inhibited 30% by 2 hours of phagocytosis and ? 50% by lactadherin-mediated engulfment. These results suggest that engulfment by macrophages and endothelial cells reduce procoagulant and fibrinolytic activity of APL blasts. Lactadherin and phagocytosis could cooperatively ameliorate the clotting disorders in APL. PMID:22138513

Xie, Rui; Gao, Chunyan; Li, Wen; Zhu, Jiuxin; Novakovic, Valerie; Wang, Jing; Ma, Ruishuang; Zhou, Jin; Gilbert, Gary E; Shi, Jialan

2012-03-01

301

A sensitive solid-phase assay for identification of class A macrophage scavenger receptor ligands using cell lysate.  

PubMed

In order for macrophages to perform their numerous homeostatic, immunological and tissue remodeling functions they are required to express a broad repertoire of cell-surface receptors. These receptors are particularly important for their host-defense functions in the recognition of foreign pathogens. Delineation of the particular functions of specific receptors requires the identification of ligands recognized by the receptor. We have developed a sensitive, high throughput, solid-phase assay for the detection of ligands for the class A macrophage scavenger receptor (SR-A). Post-nuclear cell lysate from murine bone marrow-derived macrophages is used as a source of receptor and specific ligand binding to SR-A is detected with a monoclonal antibody for SR-A. This assay has been used effectively to identify protein ligands for SR-A on the surface of the bacterium Neisseria meningitidis (Peiser, L. et al. [Peiser, L., Makepeace, K., Pluddemann, A., Savino, S., Wright, J.C., Pizza, M., Rappuoli, R., Moxon, E.R., Gordon, S., 2006. Identification of Neisseria meningitidis nonlipopolysaccharide ligands for class A macrophage scavenger receptor by using a novel assay. Infect. Immun. 74, 5191-5199]). In this paper we describe the method in detail and define the specific variables governing the assay. PMID:17996889

Plüddemann, Annette; Neyen, Claudine; Gordon, Siamon; Peiser, Leanne

2008-01-01

302

Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy  

PubMed Central

Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication. PMID:25624956

Mehraj, Vikram; Jenabian, Mohammad-Ali; Vyboh, Kishanda; Routy, Jean-Pierre

2014-01-01

303

Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses  

PubMed Central

The human-infective parasite Trichomonas vaginalis causes the most prevalent nonviral sexually transmitted infection worldwide. Infections in men may result in colonization of the prostate and are correlated with increased risk of aggressive prostate cancer. We have found that T. vaginalis secretes a protein, T. vaginalis macrophage migration inhibitory factor (TvMIF), that is 47% similar to human macrophage migration inhibitory factor (HuMIF), a proinflammatory cytokine. Because HuMIF is reported to be elevated in prostate cancer and inflammation plays an important role in the initiation and progression of cancers, we have explored a role for TvMIF in prostate cancer. Here, we show that TvMIF has tautomerase activity, inhibits macrophage migration, and is proinflammatory. We also demonstrate that TvMIF binds the human CD74 MIF receptor with high affinity, comparable to that of HuMIF, which triggers activation of ERK, Akt, and Bcl-2–associated death promoter phosphorylation at a physiologically relevant concentration (1 ng/mL, 80 pM). TvMIF increases the in vitro growth and invasion through Matrigel of benign and prostate cancer cells. Sera from patients infected with T. vaginalis are reactive to TvMIF, especially in males. The presence of anti-TvMIF antibodies indicates that TvMIF is released by the parasite and elicits host immune responses during infection. Together, these data indicate that chronic T. vaginalis infections may result in TvMIF-driven inflammation and cell proliferation, thus triggering pathways that contribute to the promotion and progression of prostate cancer. PMID:24843155

Twu, Olivia; Dessí, Daniele; Vu, Anh; Mercer, Frances; Stevens, Grant C.; de Miguel, Natalia; Rappelli, Paola; Cocco, Anna Rita; Clubb, Robert T.; Fiori, Pier Luigi; Johnson, Patricia J.

2014-01-01

304

Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages.  

PubMed

Alternative (M2) activation of macrophages driven via the ?-chain of the receptor for interleukin 4 (IL-4R?) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation. PMID:25086775

Huang, Stanley Ching-Cheng; Everts, Bart; Ivanova, Yulia; O'Sullivan, David; Nascimento, Marcia; Smith, Amber M; Beatty, Wandy; Love-Gregory, Latisha; Lam, Wing Y; O'Neill, Christina M; Yan, Cong; Du, Hong; Abumrad, Nada A; Urban, Joseph F; Artyomov, Maxim N; Pearce, Erika L; Pearce, Edward J

2014-09-01

305

A20 promotes Brucella intracellular growth via inhibition of macrophage cell death and activation.  

PubMed

The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of macrophage activation and apoptosis in tumor necrosis factor receptor1 (TNFR1) signaling pathway. Brucella infection can induce A20 expression in macrophages. Here, we hypothesize that A20 promotes Brucella intracellular growth via inhibition of activation and apoptosis of macrophages. To test this hypothesis, we stably incorporated mouse A20-shRNA into the RAW264.7 cells by lentiviral gene transfer to successfully knockdown A20. A20-deficient RAW264.7 cells were subsequently challenged with Brucella abortus and colony formation units (CFUs) of bacteria, TNF? production, NF-kB activation, macrophages apoptosis and cell death were evaluated. The A20 knockdown was shown to effectively promote B. abortus-stimulated TNF? release, NF-kB activation and macrophage cell death, which suppressed B. abortus intracellular replication. Unexpectedly, deficiency of A20 failed to lead to B. abortus-induced macrophage apoptosis. A20 deficiency coupled NF-kB inhibition promoted caspase-8 dependent B. abortus-induced macrophage apoptosis. These findings provide a novel mechanism by which Brucella intracellular growth within macrophages occurs through up-regulation of A20 thereby limiting activation and macrophages cell death. PMID:25433453

Wei, Pan; Cui, Guimei; Lu, Qiang; Yang, Li; Guan, Zhenhong; Sun, Wanchun; Zhao, Yuxi; Wang, Shuangxi; Peng, Qisheng

2015-01-30

306

Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever  

Microsoft Academic Search

Ebola hemorrhagic fever is a severe viral infection characterized by fever, shock and coagulation defects. Recent studies in macaques show that major features of illness are caused by effects of viral replication on macrophages and dendritic cells. Infected macrophages produce proinflammatory cytokines, chemokines and tissue factor, attracting additional target cells and inducing vasodilatation, increased vascular permeability and disseminated intravascular coagulation.

Mike Bray; Thomas W. Geisbert

2005-01-01

307

Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.  

PubMed Central

Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of neutrophils and their potentially histotoxic contents is one prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation. Over 24 h in culture an increasing proportion of human neutrophils from peripheral blood or acutely inflamed joints underwent morphological changes characteristic of programmed cell death or apoptosis. Time-related chromatin cleavage in an internucleosomal pattern indicative of the endogenous endonuclease activation associated with programmed cell death was also demonstrated. A close correlation was observed between the increasing properties of apoptosis in neutrophils and the degree of macrophage recognition of the aging neutrophil population, and a direct relationship between these parameters was confirmed within aged neutrophil populations separated by counterflow centrifugation into fractions with varying proportions of apoptosis. Macrophages from acutely inflamed joints preferentially ingested apoptotic neutrophils and histological evidence was presented for occurrence of the process in situ. Programmed cell death is a phenomenon of widespread biological importance and has not previously been described in a cell of the myeloid line. Because it leads to recognition of intact senescent neutrophils that have not necessarily disgorged their granule contents, these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury. Images PMID:2921324

Savill, J S; Wyllie, A H; Henson, J E; Walport, M J; Henson, P M; Haslett, C

1989-01-01

308

Detection of Fluorescent Nanoparticle Interactions with Primary Immune Cell Subpopulations by Flow Cytometry  

PubMed Central

Engineered nanoparticles are endowed with very promising properties for therapeutic and diagnostic purposes. This work describes a fast and reliable method of analysis by flow cytometry to study nanoparticle interaction with immune cells. Primary immune cells can be easily purified from human or mouse tissues by antibody-mediated magnetic isolation. In the first instance, the different cell populations running in a flow cytometer can be distinguished by the forward-scattered light (FSC), which is proportional to cell size, and the side-scattered light (SSC), related to cell internal complexity. Furthermore, fluorescently labeled antibodies against specific cell surface receptors permit the identification of several subpopulations within the same sample. Often, all these features vary when cells are boosted by external stimuli that change their physiological and morphological state. Here, 50 nm FITC-SiO2 nanoparticles are used as a model to identify the internalization of nanostructured materials in human blood immune cells. The cell fluorescence and side-scattered light increase after incubation with nanoparticles allowed us to define time and concentration dependence of nanoparticle-cell interaction. Moreover, such protocol can be extended to investigate Rhodamine-SiO2 nanoparticle interaction with primary microglia, the central nervous system resident immune cells, isolated from mutant mice that specifically express the Green Fluorescent Protein (GFP) in the monocyte/macrophage lineage. Finally, flow cytometry data related to nanoparticle internalization into the cells have been confirmed by confocal microscopy. PMID:24747480

Gamucci, Olimpia; Bertero, Alice; Malvindi, Maria Ada; Sabella, Stefania; Pompa, Pier Paolo; Mazzolai, Barbara; Bardi, Giuseppe

2014-01-01

309

Prenatal cadmium exposure alters postnatal immune cell development and function  

SciTech Connect

Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl{sub 2} (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-? production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4{sup +}FoxP3{sup +}CD25{sup +} (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8{sup +}CD223{sup +} T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific. -- Highlights: ? Prenatal exposure to Cd causes no thymocyte phenotype changes in the offspring ? Analysis of the splenocyte phenotype demonstrates a macrophage-specific effect only in male offspring ? The cytokine profiles suggest an effect on peripheral Th1 cells in female and to a lesser degree in male offspring ? There was a marked increase in serum anti-streptococcal antibody levels after immunization in both sexes ? There was a marked decrease in the numbers of splenic CD8{sup +}CD223{sup +} cells in both sexes.

Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B., E-mail: jbarnett@hsc.wvu.edu

2012-06-01

310

A novel isolation method for macrophage-like cells from mixed primary cultures of adult rat liver cells.  

PubMed

We report a simple and efficient method to obtain macrophage-like cells from the mixed primary cultures of adult rat liver cells. A parenchymal hepatocyte enriched fraction was prepared from adult rat livers and seeded into culture flasks. After 7 to 10 days of culture, when most hepatocytes were degenerated or transformed into fibroblastic cells, macrophage-like cells vigorously proliferated on the cell sheet. By shaking the flasks, macrophage-like cells were readily detached. Subsequent transfer and incubation in plastic dishes resulted in quick and selective adhesion of macrophage-like cells, while other contaminating cells remained suspended in the medium. After rinsing with saline, attached macrophage-like cells were harvested with 95 to 99% purity, as evaluated by flow cytometry or immunocytochemistry. These cells showed typical macrophage morphology and were strongly positive for markers of rat macrophages, such as ED-1, ED-3, and OX-41, but negative for cytokeratins and alpha-smooth muscle actin. They possessed functional properties of typical macrophages, including active phagocytosis of latex beads, proliferative response to recombinant GM-CSF, secretion of inflammatory and anti-inflammatory cytokines upon stimulation with LPS, and formation of multinucleated giant cells. As more than 10(6) cells can be recovered repeatedly from a T75 culture flask at two to three day intervals for more than two weeks, our procedure might implicate a novel alternative to obtain Kupffer cells in sufficient number and purity without complex equipment and skills. PMID:20600081

Kitani, Hiroshi; Takenouchi, Takato; Sato, Mitsuru; Yoshioka, Miyako; Yamanaka, Noriko

2010-08-31

311

Fine tuning inflammation at the front door: macrophage complement receptor 3-mediates phagocytosis and immune suppression for Francisella tularensis.  

PubMed

Complement receptor 3 (CR3, CD11b/CD18) is a major macrophage phagocytic receptor. The biochemical pathways through which CR3 regulates immunologic responses have not been fully characterized. Francisella tularensis is a remarkably infectious, facultative intracellular pathogen of macrophages that causes tularemia. Early evasion of the host immune response contributes to the virulence of F. tularensis and CR3 is an important receptor for its phagocytosis. Here we confirm that efficient attachment and uptake of the highly virulent Type A F. tularensis spp. tularensis strain Schu S4 by human monocyte-derived macrophages (hMDMs) requires complement C3 opsonization and CR3. However, despite a>40-fold increase in uptake following C3 opsonization, Schu S4 induces limited pro-inflammatory cytokine production compared with non-opsonized Schu S4 and the low virulent F. novicida. This suggests that engagement of CR3 by opsonized Schu S4 contributes specifically to the immune suppression during and shortly following phagocytosis which we demonstrate by CD11b siRNA knockdown in hMDMs. This immune suppression is concomitant with early inhibition of ERK1/2, p38 MAPK and NF-?B activation. Furthermore, TLR2 siRNA knockdown shows that pro-inflammatory cytokine production and MAPK activation in response to non-opsonized Schu S4 depends on TLR2 signaling providing evidence that CR3-TLR2 crosstalk mediates immune suppression for opsonized Schu S4. Deletion of the CD11b cytoplasmic tail reverses the CR3-mediated decrease in ERK and p38 activation during opsonized Schu-S4 infection. The CR3-mediated signaling pathway involved in this immune suppression includes Lyn kinase and Akt activation, and increased MKP-1, which limits TLR2-mediated pro-inflammatory responses. These data indicate that while the highly virulent F. tularensis uses CR3 for efficient uptake, optimal engagement of this receptor down-regulates TLR2-dependent pro-inflammatory responses by inhibiting MAPK activation through outside-in signaling. CR3-linked immune suppression is an important mechanism involved in the pathogenesis of F. tularensis infection. PMID:23359218

Dai, Shipan; Rajaram, Murugesan V S; Curry, Heather M; Leander, Rachel; Schlesinger, Larry S

2013-01-01

312

Human immunodeficiency virus-like particles activate multiple types of immune cells  

SciTech Connect

The rapid spread of human immunodeficiency virus (HIV) worldwide makes it a high priority to develop an effective vaccine. Since live attenuated or inactivated HIV is not likely to be approved as a vaccine due to safety concerns, HIV virus like particles (VLPs) offer an attractive alternative because they are safe due to the lack of a viral genome. Although HIV VLPs have been shown to induce humoral and cellular immune responses, it is important to understand the mechanisms by which they induce such responses and to improve their immunogenicity. We generated HIV VLPs, and VLPs containing Flt3 ligand (FL), a dendritic cell growth factor, to target VLPs to dendritic cells, and investigated the roles of these VLPs in the initiation of adaptive immune responses in vitro and in vivo. We found that HIV-1 VLPs induced maturation of dendritic cells and monocyte/macrophage populations in vitro and in vivo, with enhanced expression of maturation markers and cytokines. Dendritic cells pulsed with VLPs induced activation of splenocytes resulting in increased production of cytokines. VLPs containing FL were found to increase dendritic cells and monocyte/macrophage populations in the spleen when administered to mice. Administration of VLPs induced acute activation of multiple types of cells including T and B cells as indicated by enhanced expression of the early activation marker CD69 and down-regulation of the homing receptor CD62L. VLPs containing FL were an effective form of antigen in activating immune cells via dendritic cells, and immunization with HIV VLPs containing FL resulted in enhanced T helper type 2-like immune responses.

Sailaja, Gangadhara [Emory Vaccine Center and Department of Microbiology and Immunology, Rollins Research Center 3086, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322 (United States); Skountzou, Ioanna [Emory Vaccine Center and Department of Microbiology and Immunology, Rollins Research Center 3086, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322 (United States); Quan, Fu-Shi [Emory Vaccine Center and Department of Microbiology and Immunology, Rollins Research Center 3086, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322 (United States); Compans, Richard W. [Emory Vaccine Center and Department of Microbiology and Immunology, Rollins Research Center 3086, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322 (United States)]. E-mail: compans@microbio.emory.edu; Kang, Sang-Moo [Emory Vaccine Center and Department of Microbiology and Immunology, Rollins Research Center 3086, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322 (United States)]. E-mail: skang2@emory.edu

2007-06-05

313

Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species.  

PubMed

Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis. PMID:17909630

Gelderman, Kyra A; Hultqvist, Malin; Pizzolla, Angela; Zhao, Ming; Nandakumar, Kutty Selva; Mattsson, Ragnar; Holmdahl, Rikard

2007-10-01

314

The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma  

PubMed Central

Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGF?, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients. PMID:22190968

Tjomsland, Vegard; Niklasson, Lina; Sandström, Per; Borch, Kurt; Druid, Henrik; Bratthäll, Charlotte; Messmer, Davorka; Larsson, Marie; Spångeus, Anna

2011-01-01

315

Specific antimononuclear phagocyte monoclonal antibodies. Application to the purification of dendritic cells and the tissue localization of macrophages  

PubMed Central

3C10 and 1D9 are two related monoclonal antibodies that specifically identify human mononuclear phagocytes in a large number of sites, including blood monocytes, alveolar macrophages, and macrophages in tissue sections of spleen, lymph node, and skin. The antigen persists on monocytes cultured for greater than 4 wk, but it is not found on giant cells. The 3C10-1D9 determinant is carried by a 55 kD polypeptide, is expressed at approximately 40,000 copies per monocyte, and is protease sensitive. The antigen is clearly different from HLA- class II or Ia-like antigens that have been studied with a new monoclonal 9.3F10. The 9.3F10 antigen is found on B cells, dendritic cells and monocytes; is protease resistant, and occurs on a 33-29 kD doublet typical of class II products. The 3C10 monoclonal provides a clear distinction between human mononuclear phagocytes and dendritic cells. First, monocytes and lymphocytes can be eliminated from plastic- adherent mononuclear cells using 3C10, complement, and two previously described cytotoxic antibodies, BA-1 (anti-B cell) and Leu-1 (anti-T cell). As a result, the trace dendritic cell component of blood can be enriched to considerable purity (65-75%) and yield. Second, immunocytochemical staining of tissue sections reveals that 3C10+ macrophages are anatomically segregated from dendritic cells. Large numbers of 3C10+ cells are found in red pulp of spleen and in regions surrounding lymphatic channels of lymph node. However, 3C10+ macrophages are scarce in white pulp of spleen and the lymphocyte-rich cortex of node that are the sites where dendritic cells are localized. 3C10+ cells in skin are found in the dermis, particularly in leprosy infiltrates, but the Langerhans' cells of epidermis are 3C10-. The distinctive localization of macrophages and dendritic cells is consistent with their respective functions as effector and accessory cells in the immune response. PMID:6190974

1983-01-01

316

Francisella novicida Pathogenicity Island Encoded Proteins Were Secreted during Infection of Macrophage-Like Cells  

PubMed Central

Intracellular pathogens and other organisms have evolved mechanisms to exploit host cells for their life cycles. Virulence genes of some intracellular bacteria responsible for these mechanisms are located in pathogenicity islands, such as secretion systems that secrete effector proteins. The Francisella pathogenicity island is required for phagosomal escape, intracellular replication, evasion of host immune responses, virulence, and encodes a type 6 secretion system. We hypothesize that some Francisella novicida pathogenicity island proteins are secreted during infection of host cells. To test this hypothesis, expression plasmids for all Francisella novicida FPI-encoded proteins with C-terminal and N-terminal epitope FLAG tags were developed. These plasmids expressed their respective epitope FLAG-tagged proteins at their predicted molecular weights. J774 murine macrophage-like cells were infected with Francisella novicida containing these plasmids. The FPI proteins expressed from these plasmids successfully restored the intramacrophage growth phenotype in mutants of the respective genes that were deficient for intramacrophage growth. Using these expression plasmids, the localization of the Francisella pathogenicity island proteins were examined via immuno-fluorescence microscopy within infected macrophage-like cells. Several Francisella pathogenicity island encoded proteins (IglABCDEFGHIJ, PdpACE, DotU and VgrG) were detected extracellularly and they were co-localized with the bacteria, while PdpBD and Anmk were not detected and thus remained inside bacteria. Proteins that were co-localized with bacteria had different patterns of localization. The localization of IglC was dependent on the type 6 secretion system. This suggests that some Francisella pathogenicity island proteins were secreted while others remain within the bacterium during infection of host cells as structural components of the secretion system and were necessary for secretion. PMID:25158041

Hare, Rebekah F.; Hueffer, Karsten

2014-01-01

317

Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation  

PubMed Central

Yersinia pestis, the etiological agent of plague, is one of the most deadly pathogens on our planet. This organism shares important attributes with its ancestral progenitor, Yersinia pseudotuberculosis, including a 70-kb virulence plasmid, lymphotropism during growth in the mammalian host, and killing of host macrophages. Infections with both organisms are biphasic, where bacterial replication occurs initially with little inflammation, followed by phagocyte influx, inflammatory cytokine production, and tissue necrosis. During infection, plasmid-encoded attributes facilitate bacterial-induced macrophage death, which results from two distinct processes and corresponds to the inflammatory crescendo observed in vivo: Naïve cells die by apoptosis (noninflammatory), and later in infection, activated macrophages die by pyroptosis (inflammatory). The significance of this redirected cell death for the host is underscored by the importance of phagocyte activation for immunity to Yersinia and the protective role of pyroptosis during host responses to anthrax lethal toxin and infections with Francisella, Legionella, Pseudomonas, and Salmonella. The similarities of Y. pestis and Y. pseudotuberculosis, including conserved, plasmid-encoded functions inducing at least two distinct mechanisms of cell death, indicate that comparative studies are revealing about their critical pathogenic mechanism(s) and host innate immune responses during infection. Validation of this idea and evidence of similar interactions with the host immune system are provided by Y. pseudotuberculosis-priming, cross-protective immunity against Y. pestis. Despite these insights, additional studies indicate much remains to be understood concerning effective host responses against Yersinia, including chromosomally encoded attributes that also contribute to bacterial evasion and modulation of innate and adaptive immune responses. PMID:19734471

Bergsbaken, Tessa; Cookson, Brad T.

2009-01-01

318

A West Nile virus NS4B-P38G mutant strain induces cell intrinsic innate cytokine responses in human monocytic and macrophage cells.  

PubMed

Previous studies have shown that an attenuated West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant induces stronger innate and adaptive immune responses than wild-type WNV in mice, which has important applications to vaccine development. To investigate the mechanism of immunogenicity, we characterized WNV NS4B-P38G mutant infection in two human cell lines-THP-1 cells and THP-1 macrophages. Although the NS4B-P38G mutant produced more viral RNA than the parental WNV NY99 in both cell types, there was no detectable infectious virus in the supernatant of either cell type. Nonetheless, the attenuated mutant boosted higher innate cytokine responses than virulent parental WNV NY99 in these cells. The NS4B-P38G mutant infection of THP-1 cells led to more diverse and robust innate cytokine responses than that seen in THP-1 macrophages, which were mediated by toll-like receptor (TLR)7 and retinoic acid-inducible gene 1(RIG-I) signaling pathways. Overall, these results suggest that a defective viral life cycle during NS4B-P38G mutant infection in human monocytic and macrophage cells leads to more potent cell intrinsic innate cytokine responses. PMID:25562791

Xie, Guorui; Luo, Huanle; Tian, Bing; Mann, Brian; Bao, Xiaoyong; McBride, Jere; Tesh, Robert; Barrett, Alan D; Wang, Tian

2015-02-11

319

Hemoglobin Directs Macrophage Differentiation and Prevents Foam Cell Formation in Human Atherosclerotic Plaques  

PubMed Central

Objectives To examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis. Background Macrophage subsets are recognized in atherosclerosis but the stimulus for and importance of differentiation programs remains unknown. Methods We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage. Results Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor positive macrophages only when these cells contained hemoglobin (Hb). Cultured human monocytes exposed to hemoglobin:haptoglobin complexes (Hb:Hp), but not IL-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and upregulation of ABC transporters. M(Hb) demonstrated increased ferroportin (FPN) expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of FPN using hepcidin increased ROS, inhibited ABCA1 expression, and cholesterol efflux to ApoAI, suggesting reduced ROS triggers these effects. Knockdown of liver x receptor alpha (LXR?) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the anti-oxidant superoxide dismutase. Lastly, liver X receptor ? (LXR) luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest reduced ROS triggers LXR? activation and macrophage reverse cholesterol transport (RCT). Conclusions Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A reduction of macrophage intracellular iron plays an important role in this non- foam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXR?. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage RCT. PMID:22154776

Finn, Aloke V.; Nakano, Masataka; Polavarapu, Rohini; Karmali, Vinit; Saeed, Omar; Zhao, XiaoQing; Yazdani, Saami; Otsuka, Fumiyuki; Davis, Talina; Habib, Anwer; Narula, Jagat; Kolodgie, Frank D.; Virmani, Renu

2011-01-01

320

The cannabinoid receptors agonist WIN55212-2 inhibits macrophageal differentiation and alters expression and phosphorylation of cell cycle control proteins  

PubMed Central

In this study we investigated if and how cannabinoid receptor stimulation regulates macrophageal differentiation, which is one of the key steps in the immune effector reaction. For that reason, we used a well established differentiation model system of human U937 myelocytic leukemia cells that differentiate along the monocyte/macrophage lineage upon stimulation with the phorbol ester PMA. Constant cannabinoid receptor (CB) stimulation was performed using WIN55212-2, a potent synthetic CB agonist. We found that WIN55212-2 inhibited CB1/2-receptor-dependent PMA-induced differentiation of human myelocytic U937 cells into the macrophageal phenotype, which was associated with impaired vimentin, ICAM-1 and CD11b expression. In the presence of WIN55212-2, cdc2 protein and mRNA expression was progressively enhanced and Tyr-15-phosporylation of cdc2 was reduced in differentiating U937 cells. Additionally, p21Waf1/Cip1 expression was up-regulated. PMA-induced apoptosis was not enhanced by WIN55212-2 and differentiation-associated c-jun expression was not altered. In conclusion, we suppose that WIN55212-2-induced signals interferes with cell-cycle-arrest-signaling in differentiating myelocytic cells and thus inhibits macrophageal differentiation. Thus, it is possible that the cannabinoid system is able to influence one of the key steps in the immune effector function, the monocytic-macrophageal differentiation by alteration of cell cycle control proteins cdc2 and p21, and is therefore representing a promising option for therapeutic intervention in exacerbated immune reactions. PMID:22204398

2011-01-01

321

Characterization of an equine macrophage cell line: application to studies of EIAV infection.  

PubMed

EIAV is a monocyte/macrophage tropic virus. To date, even though EIAV has been under investigation for numerous years, very few details have been elucidated about EIAV/macrophage interactions. This is largely due to the absence of an equine macrophage cell line that would support viral replication. Herein we describe the spontaneous immortalization and generation of a clonal equine macrophage-like (EML) cell line with the functional and immunophenotype characteristics of differentiated equine monocyte derived macrophage(s) (eMDM(s)). These cells possess strong non-specific esterase (NSE) activity, are able to phagocytose fluorescent bioparticles, and produce nitrites in response to LPS. The EML-3C cell line expresses the EIAV receptor for cellular entry (ELR1) and supports replication of the virulent EIAV(PV) biological clone. Thus, EML-3C cells provide a useful cell line possessing equine macrophage related properties for the growth and study of EIAV infection as well as of other equine macrophage tropic viruses. PMID:19038510

Fidalgo-Carvalho, Isabel; Craigo, Jodi K; Barnes, Shannon; Costa-Ramos, Carolina; Montelaro, Ronald C

2009-04-14

322

Prenatal cadmium exposure alters postnatal immune cell development and function  

PubMed Central

Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl2 (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-? production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4+FoxP3+CD25+ (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8+CD223+ T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific. PMID:22521604

Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B.

2012-01-01

323

Critical Role of Macrophages and Their Activation via MyD88-NF?B Signaling in Lung Innate Immunity to Mycoplasma pneumoniae  

PubMed Central

Mycoplasma pneumoniae (Mp), a common cause of pneumonia, is associated with asthma; however, the mechanisms underlying this association remain unclear. We investigated the cellular immune response to Mp in mice. Intranasal inoculation with Mp elicited infiltration of the lungs with neutrophils, monocytes and macrophages. Systemic depletion of macrophages, but not neutrophils, resulted in impaired clearance of Mp from the lungs. Accumulation and activation of macrophages were decreased in the lungs of MyD88?/? mice and clearance of Mp was impaired, indicating that MyD88 is a key signaling protein in the anti-Mp response. MyD88-dependent signaling was also required for the Mp-induced activation of NF?B, which was essential for macrophages to eliminate the microbe in vitro. Thus, MyD88-NF?B signaling in macrophages is essential for clearance of Mp from the lungs. PMID:21203444

Lai, Jen-Feng; Zindl, Carlene L.; Duffy, Lynn B.; Atkinson, T. Prescott; Jung, Yong Woo; van Rooijen, Nico; Waites, Ken B.; Krause, Duncan C.; Chaplin, David D.

2010-01-01

324

TLR9 and RIG-I Signaling in Human Endocervical Epithelial Cells Modulates Inflammatory Responses of Macrophages and Dendritic Cells In Vitro  

PubMed Central

The innate immune system has evolved to recognize invading pathogens through pattern recognition receptors (PRRs).Among PRRs, Toll like receptors (TLRs 3, 7/8,9) and RIG-I like receptors (RLRs) have been shown to recognize viral components. Mucosal immune responses to viral infections require coordinated actions from epithelial as well as immune cells. In this respect, endocervical epithelial cells (EEC's) play an important role in initiating innate immune responses via PRRs. It is unknown whether EEC's can alter immune responses of macrophages and dendritic cells (DC's) like its counterparts in intestinal and respiratory systems. In this study, we show that endocervical epithelial cells (End1/E6E7) express two key receptors, TLR9 and RIG-I involved in anti-viral immunity. Stimulation of End1/E6E7 cells lead to the activation of NF-?B and increased secretion of pro-inflammatory cytokines, IL-6 and IL-8. Polarized End1/E6E7 cells responded to apical stimulation with ligands of TLR9 and RIG-I, CpG-ODN and Poly(I:C)LL respectively, without compromising End1/E6E7 cell integrity. At steady state, spent medium from End1/E6E7 cells significantly reduced secretion of pro-inflammatory cytokines from LPS treated human primary monocyte derived macrophages (MDMs) and DC:T cell co-cultures. Spent medium from End1/E6E7 cells stimulated with ligands of TLR9/RIG-I restored secretion of pro-inflammatory cytokines as well as enhanced phagocytosis and chemotaxis of monocytic U937 cells. Spent medium from CpG-ODN and Poly(I:C)LL stimulated End1/E6E7 cells showed significant increased secretion of IL-12p70 from DC:T cell co-cultures. The anti-inflammatory effect of spent media of End1/E6E7 cell was observed to be TGF-? dependent. In summary, the results of our study indicate that EEC's play an indispensable role in modulating anti-viral immune responses at the female lower genital tract. PMID:24409285

Sathe, Ameya; Reddy, Kudumula Venkata Rami

2014-01-01

325

cytotoxic T cells kill infected cells directly by inducing them to undergo apoptosis helper T cells help activate B cells, macrophages and cytotoxic T cells.  

E-print Network

cytotoxic T cells kill infected cells directly by inducing them to undergo apoptosis helper T cells help activate B cells, macrophages and cytotoxic T cells. Both classes of T cells express cell-surface, antibodylike receptors, encoded by genes that are assembled from multiple gene segments during T cell

Morante, Silvia

326

Indoleamine 2,3-dioxygenase-1 (IDO1) in human endometrial stromal cells induces macrophage tolerance through interleukin-33 in the progression of endometriosis.  

PubMed

In the peritoneal fluid, macrophages and their secretory cytokines are essential for endometriosis, but the factors that favor their involvement in the endometriosis-associated inflammatory response are still elusive. Given the anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) and its potentially important roles in immune modulation, we aimed to determine the effects of IDO1 in ESCs on macrophages and the mechanism of those effects. Normal ESCs and ectopic ESCs transfected with the SD11-IDO1 shRNA (short hairpin RNA) or vector-only plasmid SD11 were subsequently co-cultured with peripheral blood (PB)-derived monocytes (PBMC)-driven macrophages directly and indirectly. Cytokine production was determined by analyzing the supernatant of the co-culture unit by enzyme-linked immunosorbent assay (ELISA). The phenotypes and the phagocytic ability of the macrophages were determined by flow cytometry. Compared to normal ESCs, the PBMC-driven macrophages co-cultured with ectopic ESCs displayed lower phagocytic ability. Additionally, macrophages co-cultured with ectopic ESCs exhibited higher levels of CD163 and CD209 and lower levels of HLA-DR and CD11c. Moreover, both the intracellular expression and extracellular secretion of interleukin-10 (IL-10) and transforming growth factor-?1 (TGF-?1) were significantly increased, while that of IL-12p70 was decreased in macrophages after being co-cultured with ectopic ESCs. However, there was no significant difference in macrophage phagocytic ability, immunophenotype or cytokine secretion between the direct and indirect co-culture units. Reversely, SD11-IDO1 shRNA transfection of ectopic ESCs could abrogate the decreased phagocytic ability and alternative activation of macrophages in ectopic ESC-macrophage co-culture unit, suggesting that higher IDO1 in ectopic ESCs was indispensable for the induction of macrophage tolerance. Furthermore, the decrease in phagocytic macrophages and alternatively activated macrophages induced by IDO1 in ectopic ESCs was reversed by the addition of an IL-33 inhibitor, that is, soluble ST2 (sST2). Therefore, through the activation of IL-33, the increased expression of IDO1 in ectopic ESCs contributed to the truncated phagocytic ability of macrophages in endometriosis. PMID:25031694

Mei, Jie; Xie, Xue-Xin; Li, Ming-Qing; Wei, Chun-Yan; Jin, Li-Ping; Li, Da-Jin; Zhu, Xiao-Yong

2014-01-01

327

Imaging macrophages with nanoparticles  

NASA Astrophysics Data System (ADS)

Nanomaterials have much to offer, not only in deciphering innate immune cell biology and tracking cells, but also in advancing personalized clinical care by providing diagnostic and prognostic information, quantifying treatment efficacy and designing better therapeutics. This Review presents different types of nanomaterial, their biological properties and their applications for imaging macrophages in human diseases, including cancer, atherosclerosis, myocardial infarction, aortic aneurysm, diabetes and other conditions. We anticipate that future needs will include the development of nanomaterials that are specific for immune cell subsets and can be used as imaging surrogates for nanotherapeutics. New in vivo imaging clinical tools for noninvasive macrophage quantification are thus ultimately expected to become relevant to predicting patients' clinical outcome, defining treatment options and monitoring responses to therapy.

Weissleder, Ralph; Nahrendorf, Matthias; Pittet, Mikael J.

2014-02-01

328

Imaging macrophages with nanoparticles.  

PubMed

Nanomaterials have much to offer, not only in deciphering innate immune cell biology and tracking cells, but also in advancing personalized clinical care by providing diagnostic and prognostic information, quantifying treatment efficacy and designing better therapeutics. This Review presents different types of nanomaterial, their biological properties and their applications for imaging macrophages in human diseases, including cancer, atherosclerosis, myocardial infarction, aortic aneurysm, diabetes and other conditions. We anticipate that future needs will include the development of nanomaterials that are specific for immune cell subsets and can be used as imaging surrogates for nanotherapeutics. New in vivo imaging clinical tools for noninvasive macrophage quantification are thus ultimately expected to become relevant to predicting patients' clinical outcome, defining treatment options and monitoring responses to therapy. PMID:24452356

Weissleder, Ralph; Nahrendorf, Matthias; Pittet, Mikael J

2014-02-01

329

Regulation of the human cathelicidin antimicrobial peptide gene by 1?,25-dihydroxyvitamin D3 in primary immune cells.  

PubMed

Production of the human cathelicidin antimicrobial peptide gene (hCAP18/LL-37), is regulated by 1?,25-dihydroxyvitamin D3 (1,25D3) and is critical in the killing of pathogens by innate immune cells. In addition, secreted LL-37 binds extracellular receptors and modulates the recruitment and activity of both innate and adaptive immune cells. Evidence suggests that during infections activated immune cells locally produce increased levels of 1,25D3 thus increasing production of hCAP18/LL-37. The relative expression levels of hCAP18/LL-37 among different immune cell types are not well characterized. The aim of this study was to determine the relative levels of hCAP18/LL-37 in human peripheral blood immune cells and determine to what extent 1,25D3 increased its expression in peripheral blood-derived cells. We show for the first time, a hierarchy of expression of hCAP18 in freshly isolated cells with low levels in lymphocytes, intermediate levels in monocytes and the highest levels found in neutrophils. In peripheral blood-derived cells, the highest levels of hCAP18 following treatment with 1,25D3 were in macrophages, while comparatively lower levels were found in GM-CSF-derived dendritic cells and osteoclasts. We also tested whether treatment with parathyroid hormone in combination with 1,25D3 would enhance hCAP18 induction as has been reported in skin cells, but we did not find enhancement in any immune cells tested. Our results indicate that hCAP18 is expressed at different levels according to cell type and lineage. Furthermore, potent induction of hCAP18 by 1,25D3 in macrophages and dendritic cells may modulate functions of both innate and adaptive immune cells at sites of infection. PMID:24565560

Lowry, Malcolm B; Guo, Chunxiao; Borregaard, Niels; Gombart, Adrian F

2014-09-01

330

T-2 tetraol is cytotoxic to a chicken macrophage cell line.  

PubMed

Cytotoxic effects of T-2 tetraol, a T-2 toxin derivative, on the MQ-NCSU chicken macrophage cell line were quantified by direct in vitro exposure. Macrophage cultures were exposed to 1, 10, 20, 40, 80, 160, and 320 micrograms/mL of T-2 tetraol for 1 h. Macrophage viability after exposure to T-2 tetraol. Macrophage viability was reduced by increasing concentrations of T-2 tetraol (linear effect, P < or = 0.001; quadratic effect, P < or = 0.025). The ability of macrophages to adhere to glass surfaces was impaired by increasing concentrations of T-2 tetraol (linear effect, P < or = 0.003). This experiment demonstrates that T-2 tetraol is cytotoxic to chicken macrophages in vitro. PMID:9057211

Kidd, M T; Qureshi, M A; Hagler, W M; Ali, R

1997-02-01

331

Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques.  

PubMed Central

Lipoprotein lipase (LPL), hydrolyzes the core triglycerides of lipoproteins, thereby playing a role in their maturation. LPL may be important in the metabolic pathways that lead to atherosclerosis, since it is secreted in vitro by both of the predominant cell types of the atherosclerotic plaque, i.e., macrophages and smooth muscle cells. Because of uncertainty concerning the primary cellular source of LPL in atherosclerotic lesions, in situ hybridization assays for LPL mRNA were performed on 12 coronary arteries obtained from six cardiac allograft recipients. Macrophages and smooth muscle cells were identified on adjacent sections with cell-specific antibodies and foam cells were identified morphologically. LPL protein was localized using a polyclonal antibody. LPL mRNA was produced by a proportion of plaque macrophages, particularly macrophage-derived foam cells, but was not detected in association with any intimal or medial smooth muscle cells. These findings were confirmed by combined immunocytochemistry and in situ hybridization on the same tissue sections. LPL protein was detected in association with macrophage-derived foam cells, endothelial cells, adventitial adipocytes, and medial smooth muscle cells, and, to a lesser extent, in intimal smooth muscle cells and media underlying well-developed plaque. These results indicate that macrophage-derived foam cells are the primary source of LPL in atherosclerotic plaques and are consistent with a role for LPL in the pathogenesis of atherosclerosis. Images PMID:1569193

O'Brien, K D; Gordon, D; Deeb, S; Ferguson, M; Chait, A

1992-01-01

332

Innate Immune Responses to Lung-Stage Helminth Infection Induce Alternatively Activated Alveolar Macrophages  

Microsoft Academic Search

While it is well established that infection with the rodent hookworm Nippostrongylus brasiliensis induces a strongly polarized Th2 immune response, little is known about the innate host-parasite interactions that lead to the development of this robust Th2 immunity. We exploited the transient pulmonary phase of N. brasiliensis development to study the innate immune responses induced by this helminth parasite in

Joshua J. Reece; Mark C. Siracusa; Alan L. Scott

2006-01-01

333

Comprehensive proteomic data sets for studying adipocyte-macrophage cell-cell communication.  

PubMed

Cellular communication is a fundamental process in biology. The interaction of adipocytes with macrophages is a key event in the development of common diseases such as type 2 diabetes. We applied an established bilayer cell co-culture system and comprehensive mass spectrometry analysis to detect proteome-wide the paracrine interaction of murine adipocytes and macrophages. Altogether, we identified 4486 proteins with at least two unique peptides of which 2392 proteins were informative for 3T3-L1 adipocytes and 2957 proteins for RAW 264.7 macrophages. Further, we observed over 12,000 phosphorylation sites of which we could assign 3,200 informative phosphopeptides with a single phosphosite for adipocytes and 4,514 for macrophages. Using protein set enrichment and phosphosite analyses, we deciphered regulatory protein pathways involved in cellular stress and inflammation, which can contribute to metabolic impairment of cells including insulin resistance and other disorders. The generated data sets provide a holistic, molecular pathway-centric view on the interplay of adipocytes and macrophages in disease processes and a resource for further studies. PMID:24174276

Freiwald, Anja; Weidner, Christopher; Witzke, Annabell; Huang, Sheng-Yu; Meierhofer, David; Sauer, Sascha

2013-12-01

334

Cell mechanics of alveolar epithelial cells (AECs) and macrophages (AMs)  

Microsoft Academic Search

Cell mechanics provides an integrated view of many biological phenomena which are intimately related to cell structure and function. Because breathing constitutes a sustained motion synonymous with life, pulmonary cells are normally designed to support permanent cyclic stretch without breaking, while receiving mechanical cues from their environment. The authors study the mechanical responses of alveolar cells, namely epithelial cells and

Sophie Féréol; Redouane Fodil; Gabriel Pelle; Bruno Louis; Daniel Isabey

2008-01-01

335

In Vitro Cytotoxicity of Silver Nanomaterials in Murine Macrophages  

EPA Science Inventory

Silver nanomaterials are increasingly used as antimicrobial agents in a variety of products. Although there is considerable potential for human exposure to these nanomaterials, little is known about the health risks associated with their use. Macrophages are prominent immune cell...

336

The immune potential and immunopathology of cytokine-producing B cell subsets: A comprehensive review.  

PubMed

B lymphocytes are generally recognized for their potential to mediate humoral immunity by producing different antibody isotypes and being involved in opsonization and complement fixation. Nevertheless, the non-classical, antibody-independent immune potential of B cell subsets has attracted much attention especially in the past decade. These B cells can release a broad variety of cytokines (such as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-?, IFN-?, TNF-?, TGF-?, LT), and can be classified into distinct subsets depending on the particular cytokine profile, thus emerging the concept of cytokine-producing B cell subsets. Although there is still controversy surrounding the key cell surface markers, intracellular factors and cellular origins of cytokine-producing B cell subsets, accumulating evidence indicates that these B cells are endowed with great potential to regulate both innate and adaptive arms of immune system though releasing cytokines. On the one hand, they promote immune responses through mounting Th1/Th2/Th17 and neutrophil response, inducing DC maturation and formation of lymphoid structures, increasing NK cell and macrophage activation, enhancing development of themselves and sustaining antibody production. On the other hand, they can negatively regulate immune responses by suppressing Th cell responses, inhibiting Tr1 cell and Foxp3(+) Treg differentiation, impairing APC function and pro-inflammatory cytokine release by monocytes, and inducing CD8(+) T cell anergy and CD4(+) T cell apoptosis. Therefore, cytokine-producing B cell subsets have multifunctional functions in health and diseases, playing pathologic as well as protective roles in autoimmunity, infection, allergy, and even malignancy. In this review, we revisit the history of discovering cytokine-producing B cells, describe the identification of cytokine-producing B cell subsets, introduce the origins of cytokine-producing B cell subsets as well as molecular and cellular mechanisms for their differentiation, and summarize the recent progress made toward understanding the unexpectedly complex and potentially opposing roles of cytokine-producing B cells in immunological disorders. PMID:24794622

Bao, Yan; Cao, Xuetao

2014-12-01

337

IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.  

PubMed

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease. PMID:24572363

Shen, Ping; Roch, Toralf; Lampropoulou, Vicky; O'Connor, Richard A; Stervbo, Ulrik; Hilgenberg, Ellen; Ries, Stefanie; Dang, Van Duc; Jaimes, Yarúa; Daridon, Capucine; Li, Rui; Jouneau, Luc; Boudinot, Pierre; Wilantri, Siska; Sakwa, Imme; Miyazaki, Yusei; Leech, Melanie D; McPherson, Rhoanne C; Wirtz, Stefan; Neurath, Markus; Hoehlig, Kai; Meinl, Edgar; Grützkau, Andreas; Grün, Joachim R; Horn, Katharina; Kühl, Anja A; Dörner, Thomas; Bar-Or, Amit; Kaufmann, Stefan H E; Anderton, Stephen M; Fillatreau, Simon

2014-03-20

338

The Antiviral Effect of High-Molecular Weight Poly-Gamma-Glutamate against Newcastle Disease Virus on Murine Macrophage Cells  

PubMed Central

This study demonstrates the capacity of HM-?-PGA treatment to significantly protect murine macrophage cells (RAW 264.7 cells) against NDV infection. Such protection can be explained by the induction of antiviral state of HM-?-PGA in RAW 264.7 cells via TLR4-mediated IRF-3, IRF-7, IFN-?, and IFN-related gene induction as shown in time-dependent changes in mRNA expression confirmed by polymerase chain reaction (PCR). Moreover, the present research also showed that HM-?-PGA can induce proinflammatory cytokine secretion in RAW 264.7 as measured by enzyme-linked immunosorbent assay (ELISA). Therefore, our findings suggest that HM-?-PGA can be a potential antiviral substance that can inhibit NDV infection through its stimulation of antiviral state on RAW 264.7 cells. These results have been consistent with the previous studies showing that HM-?-PGA can protect RAW 264.7 cells and mice against influenza infection. However, it should be noted that although murine macrophage cells are susceptible to NDV, they are not the natural host cells of the virus; thus further in vivo and in vitro studies involving chicken and chicken immune cells are needed to fully assess the efficacy and applicability of HM-?-PGA in the poultry industry. PMID:25610463

Talactac, Melbourne; Lee, Jong-Soo; Moon, Hojin; Chowdhury, Mohammed Y. E.; Kim, Chul Joong

2014-01-01

339

Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing  

PubMed Central

Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to enhance wound healing; however, the mechanisms involved are barely understood. In this study, we examined paracrine factors released by BM-MSCs and their effects on the cells participating in wound healing compared to those released by dermal fibroblasts. Analyses of BM-MSCs with Real-Time PCR and of BM-MSC-conditioned medium by antibody-based protein array and ELISA indicated that BM-MSCs secreted distinctively different cytokines and chemokines, such as greater amounts of VEGF-?, IGF-1, EGF, keratinocyte growth factor, angiopoietin-1, stromal derived factor-1, macrophage inflammatory protein-1alpha and beta and erythropoietin, compared to dermal fibroblasts. These molecules are known to be important in normal wound healing. BM-MSC-conditioned medium significantly enhanced migration of macrophages, keratinocytes and endothelial cells and proliferation of keratinocytes and endothelial cells compared to fibroblast-conditioned medium. Moreover, in a mouse model of excisional wound healing, where concentrated BM-MSC-conditioned medium was applied, accelerated wound healing occurred compared to administration of pre-conditioned or fibroblast-conditioned medium. Analysis of cell suspensions derived from the wound by FACS showed that wounds treated with BM-MSC-conditioned medium had increased proportions of CD4/80-postive macrophages and Flk-1-, CD34- or c-kit-positive endothelial (progenitor) cells compared to wounds treated with pre-conditioned medium or fibroblast-conditioned medium. Consistent with the above findings, immunohistochemical analysis of wound sections showed that wounds treated with BM-MSC-conditioned medium had increased abundance of macrophages. Our results suggest that factors released by BM-MSCs recruit macrophages and endothelial lineage cells into the wound thus enhancing wound healing. PMID:18382669

Chen, Liwen; Tredget, Edward E.; Wu, Philip Y. G.; Wu, Yaojiong

2008-01-01

340

The effects of vitamin D binding protein-macrophage activating factor and colony-stimulating factor-1 on hematopoietic cells in normal and osteopetrotic rats.  

PubMed

Osteopetrosis is a heterogeneous group of bone disorders characterized by the failure of osteoclasts to resorb bone and by several immunological defects including macrophage dysfunction. Two compounds, colony-stimulating factor-1 (CSF-1) and vitamin D-binding protein-macrophage activating factor (DBP-MAF) were used in the present study to evaluate their effects on the peritoneal population of cells and on cells within the bone marrow microenvironment in normal and incisors absent (ia) osteopetrotic rats. Previous studies in this laboratory have demonstrated that administration of DBP-MAF to newborn ia animals results in a substantial increase in bone marrow cavity size due to upregulated osteoclast function. To study the effects of these compounds on the macrophage/osteoclast precursors, DBP-MAF, CSF-1, and the combination of these compounds were given to newborn ia and normal littermate animals. Both the normal and mutant phenotypes responded similarly when treated with these compounds. Rats exhibited a profound shift toward the macrophage lineage from the neutrophil lineage when compared with vehicle-treated control animals after treatment with these compounds. In the in vivo peritoneal lavage study, animals received injections of CSF-1, DBP-MAF or DBP-MAF/CSF-1 over a 4-week period. The various types of cells in the peritoneal cavity were then enumerated. The in vitro study consisted of cells isolated from the bone marrow microenvironment and cultured on feeder layers of CSF-1, DBP-MAF, or DBP-MAF/CSF-1 for colony enumeration. The increase in macrophage numbers at the expense of neutrophil numbers could be seen in both the in vivo and in vitro experiments. The macrophage/osteoclast and neutrophil lineages have a common precursor, the granulocyte/macrophage colony-forming cell (GM-CFC). With the addition of CSF-1, the GM-CFC precursor may be induced into the macrophage/osteoclast lineage rather than the granulocyte lineage. This increased pool of cells in the macrophage/osteoclast lineage can be functionally upregulated with the subsequent addition of DBP-MAF to perform the activities of phagocytosis and bone resorption. The in vitro data also showed that DBP-MAF did not support colony development as in CSF-1 or the combination treatment. The recruitment and activation of cells into the macrophage/ osteoclast lineage may help to correct the bone and immune defects found in diseases demonstrating a significant lack of myeloid cells, as well as neutrophilia disorders and the disease, osteopetrosis. PMID:8874186

Benis, K A; Schneider, G B

1996-10-15

341

Regulation of hematopoietic and leukemic stem cells by the immune system  

PubMed Central

Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4+ and CD8+ T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs. PMID:24992931

Riether, C; Schürch, C M; Ochsenbein, A F

2015-01-01

342

Primary Human Splenic Macrophages, but Not T or B Cells, Are the Principal Target Cells for Dengue Virus Infection In Vitro?  

PubMed Central

Understanding the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) requires the precise identification of dengue virus (DV)-permissive target cells. In a previous study using unfractionated human peripheral blood mononuclear cells, we found that monocytes, but not B or T cells, were the principal DV-permissive cells in the absence of DV-immune pooled human sera (PHS) and the major mediators of antibody-dependent enhancement in the presence of PHS. To further identify DV-permissive target cells in other tissues and organs, we isolated human splenic mononuclear cells (MNCs), inoculated them with DV type 2 (strain 16681) in the presence or absence of PHS, and assessed their infection either directly using flow cytometry and reverse transcription-PCR (RT-PCR) assays or indirectly by plaque assay. We found that in the absence of PHS, a small proportion of splenic macrophages appeared to be positive for DV antigens in comparison to staining controls by the flow cytometric assay (0.77% ± 1.00% versus 0.18% ± 0.12%; P = 0.07) and that viral RNA was detectable by the RT-PCR assay in MNCs exposed to DV. Additionally, supernatants from cultures of DV-exposed MNCs contained infectious virions that were readily detectable by plaque assay. The magnitude of infection was significantly enhanced in splenic macrophages in the presence of highly diluted PHS (5.41% ± 3.53% versus 0.77% ± 1.00%; P = 0.001). In contrast, primary T and B cells were not infected in either the presence or absence of PHS. These results provide evidence, for the first time, that human primary splenic macrophages, rather than B or T cells, are the principal DV-permissive cells in the spleen and that they may be uniquely important in the initial steps of immune enhancement that leads to DHF/DSS in some DV-infected individuals. PMID:17928355

Blackley, Shanley; Kou, Zhihua; Chen, Huiyuan; Quinn, Matthew; Rose, Robert C.; Schlesinger, Jacob J.; Coppage, Myra; Jin, Xia

2007-01-01

343

An MHC Class II Dependent Activation Loop Between Adipose Tissue Macrophages and CD4+ T cells Controls Obesity-Induced Inflammation  

PubMed Central

Summary An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4+ T cells by unclear mechanisms. We have examined if interactions between adipose tissue macrophages (ATMs) and CD4+ T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHCII) showed protection from diet-induced obesity. Deletion of MHCII expression in macrophages led to an adipose tissue specific decrease in the effector/memory CD4+ T cells, attenuation of CD11c+ ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c+ ATMs in obese mice. These studies demonstrate the importance of MHC Class II restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation. PMID:25310975

Cho, Kae Won; Morris, David L.; DelProposto, Jennifer L.; Geletka, Lynn; Zamarron, Brian; Martinez-Santibanez, Gabriel; Meyer, Kevin A.; Singer, Kanakadurga; O'Rourke, Robert W.; Lumeng, Carey N.

2014-01-01

344

Macrophage cell lines derived from major histocompatibility complex II-negative mice  

NASA Technical Reports Server (NTRS)

Two bone-marrow-derived macrophage cell lines, C2D and C2Dt, were isolated from major histocompatibility class II negative knock-out mice. The C2D cell line was stabilized by continuous culture in colony-stimulating factor-1 and the C2Dt cell line was transformed with SV40 virus large T antigen. These cells exhibited phenotypic properties of macrophages including morphology and expression of Mac 1 and Mac 2 cell surface molecules. These cells also had comparable growth to the bone-marrow-derived macrophage cell line B6MP102. These new cell lines were not spontaneously cytotoxic and were only capable of modest killing of F5b tumor cells when stimulated with LPS and interferon-gamma, but not when stimulated with LPS alone or with staphylococcal exotoxin. C2D and C2Dt cells phagocytosed labeled Staphylococcus aureus similarly to B6MP102 cells but less well than C2D peritoneal macrophages. These cell lines secreted interleukin-6, but not tumor necrosis factor or nitric oxide in response to LPS or staphlococcal enterotoxins A or B C2D(t) cells were tumorigenic in C2D and C57BL/6J mice but C2D cells were not. These data suggest that macrophage cell lines can be established from bone marrow cells of major histocompatibility complex II-negative mice.

Beharka, A. A.; Armstrong, J. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1998-01-01

345

IRF3 polymorphisms induce different innate anti-Theiler's virus immune responses in RAW264.7 macrophages  

SciTech Connect

Persistent viral infections can lead to disease such as myocarditis. Theiler's murine encephalomyelitis virus (TMEV) infects macrophages of SJL/J (H-2s) mice establishing persistent infections leading to demyelinating disease. In contrast macrophages from B10.S (H-2s) mice clear TMEV. Activation of the transcription factor IRF3 induces IFN{beta}, ISG56, and apoptosis for viral clearance, but also inflammatory cytokines, such as IL-23 and IL6, which contribute to disease. Here we identify polymorphisms in the IRF3 of SJL/J versus B10.S mice that are located in DNA binding, nuclear localization, and autoinhibitory domains. SJL-IRF3 expression in RAW264.7 macrophage cells with or without TMEV infection decreased IL-23p19 promoter activity compared with B10S-IRF3. In contrast SJL-IRF3 increased IL-6, ISG56 and IFN{beta} in response to TMEV. B10S-IRF3 expression augmented apoptotic caspase activation and decreased viral RNA in TMEV-infected macrophages while SJL-IRF3 increased viral replication with less caspase activation. Therefore IRF3 polymorphisms contribute to viral persistence and altered cytokine expression.

Moore, Tyler C. [School of Biological Sciences, University of Nebraska Lincoln (United States); Al-Salleeh, Fahd M. [Endodontics, University of Nebraska Medical Center (United States); Brown, Deborah M. [School of Biological Sciences, University of Nebraska Lincoln (United States); Nebraska Center for Virology, University of Nebraska Lincoln (United States); Petro, Thomas M., E-mail: tpetro@unmc.edu [Nebraska Center for Virology, University of Nebraska Lincoln (United States); Departments of Oral Biology, University of Nebraska Medical Center (United States)

2011-09-15

346

How Do Immune Cells Support and Shape the Brain in Health, Disease, and Aging?  

PubMed Central

For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed. PMID:24198349

Kipnis, Jonathan; Rivest, Serge; Prat, Alexandre

2013-01-01

347

How do immune cells support and shape the brain in health, disease, and aging?  

PubMed

For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed. PMID:24198349

Schwartz, Michal; Kipnis, Jonathan; Rivest, Serge; Prat, Alexandre

2013-11-01

348

The role of melatonin in the cells of the innate immunity: a review.  

PubMed

Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. In recent years, a considerable amount of experimental evidence has accumulated showing a relationship between the nervous, endocrine, and immune systems. The molecular basis of the communication between these systems is the use of a common chemical language. In this framework, currently melatonin is considered one of the members of the neuroendocrine-immunological network. A number of in vivo and in vitro studies have documented that melatonin plays a fundamental role in neuroimmunomodulation. Based on the information published, it is clear that the majority of the present data in the literature relate to lymphocytes; thus, they have been rather thoroughly investigated, and several reviews have been published related to the mechanisms of action and the effects of melatonin on lymphocytes. However, few studies concerning the effects of melatonin on cells belonging to the innate immunity have been reported. Innate immunity provides the early line of defense against microbes and consists of both cellular and biochemical mechanisms. In this review, we have focused on the role of melatonin in the innate immunity. More specifically, we summarize the effects and action mechanisms of melatonin in the different cells that belong to or participate in the innate immunity, such as monocytes-macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, and natural killer cells. PMID:23889107

Calvo, Juan R; González-Yanes, C; Maldonado, M D

2013-09-01

349

Bone morphogenetic protein-6 induces castration resistance in prostate cancer cells through tumor infiltrating macrophages.  

PubMed

Bone morphogenetic protein (BMP) is a pleiotropic growth factor that has been implicated in inflammation and prostate cancer (CaP) progression. We investigated the potential role of BMP-6 in the context of macrophages and castration-resistant prostate cancer. When the androgen-responsive murine (Tramp-C1 and PTENCaP8) and human (LNCaP) CaP cell lines were cocultured with macrophages in the presence of dihydrotestosterone, BMP-6 increased androgen-responsive promoter activity and cell count significantly. Subsequent studies revealed that BMP-6 increased the expression level of androgen receptor (AR) mRNA and protein in CaP cell lines only in the presence of macrophages. Simultaneously, the AR antagonists bicalutamide and MDV3100 partially or completely blocked BMP-6-induced macrophage-mediated androgen hypersensitivity in CaP cells. Abolishing interleukin-6 signaling with neutralizing antibody in CaP/macrophage cocultures inhibited the BMP-6-mediated AR upregulation in CaP cells. Using Tramp-C1 and PTENCaP8 cells with a tetracycline-inducible expression of BMP-6, the induction of BMP-6 in vivo resulted in a significant resistance to castration. However, this resistance was blocked after the removal of macrophages with clodronate liposomes. Taken together, these results show that BMP-6 induces castration resistance by increasing the expression of AR through macrophage-derived interleukin-6. PMID:23710822

Lee, Geun Taek; Jung, Yeon Suk; Ha, Yun-Sok; Kim, Jeong Hyun; Kim, Wun-Jae; Kim, Isaac Y

2013-08-01

350

Calcium signaling in immune cells  

PubMed Central

Calcium acts as a second messenger in many cell types, including lymphocytes. Resting lymphocytes maintain a low concentration of Ca2+. However, engagement of antigen receptors induces calcium influx from the extracellular space by several routes. A chief mechanism of Ca2+ entry in lymphocytes is through store-operated calcium (SOC) channels. The identification of two important molecular components of SOC channels, CRACM1 (the pore-forming subunit) and STIM1 (the sensor of stored calcium), has allowed genetic and molecular manipulation of the SOC entry pathway. In this review, we highlight advances in the understanding of Ca2+ signaling in lymphocytes with special emphasis on SOC entry. We also discuss outstanding questions and probable future directions of the field. PMID:19088738

Vig, Monika; Kinet, Jean-Pierre

2010-01-01

351

Characterization of Salmonella-Induced Cell Death in Human Macrophage-Like THP1 Cells  

Microsoft Academic Search

Salmonella strains are facultative intracellular pathogens that produce marked cytopathology during infec- tion of host cells. Different forms of cytopathic effects have been associated with the virulence systems encoded by the two Salmonella pathogenicity islands (SPI-1 and SPI-2) and the spv locus. We used Salmonella enterica serovar Dublin to investigate the induction of cytopathology during infection of the human macrophage-like

Eulalia Valle; Donald G. Guiney

2005-01-01

352

Macrophage migration inhibitory factor (MIF) of the protozoan parasite Eimeria influences the components of the immune system of its host, the chicken.  

PubMed

Macrophage migration inhibitory factor (MIF) is a soluble factor produced by sensitized T lymphocytes that inhibits the random migration of macrophages. Homologues of MIF from invertebrates have been identified, making it an interesting molecule from a functional perspective. In the present study, the localization of a parasite MIF protein as well as its effect on the host was characterized. Western blot analysis shows that Eimeria MIF (EMIF) is found during all parasite developmental stages tested. Transmission electron microscopy shows that MIF is distributed throughout cytosol and nucleus of Eimeria acervulina merozoites. Immunohistochemical analysis suggests that EMIF may be released into the surrounding tissues as early as 24 h after infection, while later during oocyst formation, MIF expression is localized to areas immediately surrounding the oocysts, as well as in wall-forming bodies. The chemotaxis assay revealed an inhibitory function of EMIF on chicken monocyte migration. Quantitative real-time PCR was performed to examine the effect of EMIF on host immune system by measuring the transcripts of inflammatory mediators. An ex vivo stimulation study showed that E. acervulina MIF (EaMIF) enhanced expression of pro-inflammatory cytokines and chemokines in the presence of lipopolysaccharide (LPS). Furthermore, sequential treatment of adherent peripheral blood mononuclear cells with EaMIF, chicken MIF, and LPS in 2-h intervals led to the highest levels of interleukin (IL)-1B, chemokine CCLi3, IL-18, and interferon-gamma mRNA expression. This study shows that parasite MIF is widely expressed and may have potential effects on the immune system of the host. PMID:23435923

Miska, Katarzyna B; Kim, Sungwon; Fetterer, Raymond H; Dalloul, Rami A; Jenkins, Mark C

2013-05-01

353

Impact of Plasmids, Including Those EncodingVirB4/D4 Type IV Secretion Systems, on Salmonella enterica serovar Heidelberg Virulence in Macrophages and Epithelial Cells  

PubMed Central

Salmonella enterica serovar Heidelberg (S. Heidelberg) can cause foodborne illness in humans following the consumption of contaminated meat and poultry products. Recent studies from our laboratory have demonstrated that certain S. Heidelberg isolated from food-animal sources harbor multiple transmissible plasmids with genes that encode antimicrobial resistance, virulence and a VirB4/D4 type-IV secretion system. This study examines the potential role of these transmissible plasmids in bacterial uptake and survival in intestinal epithelial cells and macrophages, and the molecular basis of host immune system modulation that may be associated with disease progression. A series of transconjugant and transformant strains were developed with different combinations of the plasmids to determine the roles of the individual and combinations of plasmids on virulence. Overall the Salmonella strains containing the VirB/D4 T4SS plasmids entered and survived in epithelial cells and macrophages to a greater degree than those without the plasmid, even though they carried other plasmid types. During entry in macrophages, the VirB/D4 T4SS encoding genes are up-regulated in a time-dependent fashion. When the potential mechanisms for increased virulence were examined using an antibacterial Response PCR Array, the strain containing the T4SS down regulated several host innate immune response genes which likely contributed to the increased uptake and survival within macrophages and epithelial cells. PMID:24098597

Gokulan, Kuppan; Khare, Sangeeta; Rooney, Anthony W.; Han, Jing; Lynne, Aaron M.; Foley, Steven L.

2013-01-01

354

Myeloid Cell TRAF3 Regulates Immune Responses and Inhibits Inflammation and Tumor Development in Mice.  

PubMed

Myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNFR and TLR families, whose signals are transduced by TNFR-associated factor (TRAF) molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I IFN production, but the in vivo function of TRAF3 in myeloid cells remains unknown. In this article, we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3(-/-)) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-?B2 activation. However, in response to injections with LPS (a bacterial mimic) or polyinosinic-polycytidylic acid (a viral mimic), M-TRAF3(-/-) mice exhibited an altered profile of cytokine production. M-TRAF3(-/-) mice immunized with T cell-independent and -dependent Ags displayed elevated T cell-independent IgG3 and T cell-dependent IgG2b responses. Interestingly, 15- to 22-mo-old M-TRAF3(-/-) mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice. PMID:25422508

Lalani, Almin I; Moore, Carissa R; Luo, Chang; Kreider, Benjamin Z; Liu, Yan; Morse, Herbert C; Xie, Ping

2015-01-01

355

Melanoma-initiating cells exploit M2 macrophage TGF? and arginase pathway for survival and proliferation.  

PubMed

M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34- but not CD34+ tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34- TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34- TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-? (TGF?) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth. PMID:25294815

Tham, Muly; Tan, Kar Wai; Keeble, Jo; Wang, Xiaojie; Hubert, Sandra; Barron, Luke; Tan, Nguan Soon; Kato, Masashi; Prevost-Blondel, Armelle; Angeli, Veronique; Abastado, Jean-Pierre

2014-12-15

356

Melanoma-initiating cells exploit M2 macrophage TGF? and arginase pathway for survival and proliferation  

PubMed Central

M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell