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1

Activated macrophages as effector cells of protective immunity to schistosomiasis  

Microsoft Academic Search

Conclusion  The study of macrophage-schistosome interaction has yielded insights into the mechanism of macrophage cytotoxicity against\\u000a extracellular targets, as well as the generation of cell-mediated immunity in infectious disease. Many of the results surveyed\\u000a here emphasize the similarities in conditions for induction and expression of macrophage function; for example, (1) conditions\\u000a inducing macrophage activation for killing of schistosomula or tumor cells

Stephanie L. James

1986-01-01

2

PDT-apoptotic tumor cells induce macrophage immune response  

NASA Astrophysics Data System (ADS)

Photodynamic therapy (PDT) functions as a cancer therapy through two major cell death mechanisms: apoptosis and necrosis. Immunological responses induced by PDT has been mainly associated with necrosis while apoptosis associated immune responses have not fully investigated. Heat shock proteins (HSPs) play an important role in regulating immune responses. In present study, we studied whether apoptotic tumor cells could induce immune response and how the HSP70 regulates immune response. The endocytosis of tumor cells by the activated macrophages was observed at single cell level by LSM. The TNF-? release of macrophages induced by co-incubated with PDT-apoptotic tumor cells was detected by ELISA. We found that apoptotic tumor cells treated by PDT could activate the macrophages, and the immune effect decreased evidently when HSP70 was blocked. These findings not only show that apoptosis can induce immunological responses, but also show HSP70 may serves as a danger signal for immune cells and induce immune responses to regulate the efficacy of PDT.

Zhou, Fei-fan; Xing, Da; Chen, Wei R.

2008-03-01

3

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

Microsoft Academic Search

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

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

2010-01-01

4

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...

5

Sequestration from Immune CD4^+ T Cells of Mycobacteria Growing in Human Macrophages  

NASA Astrophysics Data System (ADS)

CD4^+ helper T cells mediate resistance to tuberculosis, presumably by enhancing the antimicrobial activity of macrophages within which the Mycobacterium tuberculosis organism grows. A first step in resistance should be the presentation of mycobacterial antigens by macrophages to CD4^+ T cells. However, when the antigenic stimulus is limited to organisms growing in human monocytes, the organisms become sequestered from immune CD4^+ T cells. This block in presentation is selective for growing mycobacteria and not for other stimuli. Sequestration would allow replicating organisms to persist in infected individuals and may contribute to virulence.

Pancholi, Preeti; Mirza, Asra; Bhardwaj, Nina; Steinman, Ralph M.

1993-05-01

6

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.

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

2010-01-01

7

Macrophages as effector cells of protective immunity in murine schistosomiasis. VI. T cell-dependent, lymphokine-mediated, activation of macrophages in response to Schistosoma mansoni antigens.  

PubMed

Macrophages from Schistosoma mansoni-infected mice kill significant numbers of skin stage schistosomula and murine fibrosarcoma cells in vitro. In order to determine whether the macrophage tumoricidal and larvicidal activation observed in mice as a result of S. mansoni infection are mediated through T cell-dependent (lymphokine) or B cell-dependent (antibody or immune complex) mechanisms, the development of macrophage populations with cytotoxic activity against schistosome larvae or tumor cells was monitored in S. mansoni-infected nude or mu-suppressed mice. Whereas peritoneal cells from S. mansoni-infected congenitally athymic mice had no activity in either assay, cells from mu-suppressed S. mansoni-infected mice showed cytotoxic activity equivalent to that of cells from untreated S. mansoni-infected counterparts. Cells from mu-suppressed uninfected mice were not activated. The mu-suppressed animals had no detectable nonspecific IgM or specific antischistosome IgM, IgG, or IgE antibodies and showed a 90% reduction in numbers of splenic IgM+ cells upon fluorescence activated cell sorter analysis. These results indicate that antibody is not required for in vivo activation of macrophages during S. mansoni infection. Further experiments showed that lymphoid cells from S. mansoni infected mice respond in culture with various specific antigens (such as living or dead whole schistosomula or soluble adult worm antigens) by production of factors capable of activating macrophages from uninfected control mice to kill schistosomula or tumor cells in vitro. Macrophage-activating factors were produced by T cell-enriched, but not T cell-depleted or B cell-enriched, populations from spleens of schistosome-infected mice in response to schistosome antigen. Similar lymphokines may be responsible for the macrophage activation observed during chronic murine schistosomiasis. These observations emphasize the potential contribution of T cell-mediated immune mechanisms in resistance to S. mansoni infection. PMID:6350456

James, S L; Lazdins, J K; Hieny, S; Natovitz, P

1983-09-01

8

Differential Clearance and Immune Responses to Tick Cell-Derived versus Macrophage Culture-Derived Ehrlichia chaffeensis in Mice  

Microsoft Academic Search

Human monocytic ehrlichiosis is caused by a tick-transmitted rickettsia, Ehrlichia chaffeensis. We recently reported that E. chaffeensis grown in tick cells expresses different proteins than bacteria grown in macrophages. Therefore, we tested the hypothesis that immune responses against E. chaffeensis would be different if the mice are challenged with bacteria grown in macrophages or tick cells. We assessed the E.

Roman R. Ganta; Chuanmin Cheng; Elizabeth C. Miller; Bridget L. McGuire; Lalitha Peddireddi; Kamesh R. Sirigireddy; Stephen K. Chapes

2007-01-01

9

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

PubMed

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; Ho, Wenzhe

2013-02-11

10

Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse  

SciTech Connect

Purpose: This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. Methods and materials: RAW 264.7 macrophages were activated by lipid A, and the conditioned medium (CM) was analyzed for the secretion of cytokines and the production of nitric oxide (NO) through inducible nitric oxide synthase (iNOS). EMT-6 tumor cells were exposed to CM and analyzed for hypoxic cell radiosensitivity. The role of nuclear factor (NF)-{kappa}B in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Results: Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 {mu}g/mL, stimulated RAW 264.7 macrophages to release NO, tumor necrosis factor (TNF)-{alpha}, and other cytokines. This in turn activated iNOS-mediated NO production in EMT-6 tumor cells and drastically enhanced their radiosensitivity. Radiosensitization was abrogated by the iNOS inhibitor aminoguanidine but not by a neutralizing anti-TNF-{alpha} antibody. The mechanism of iNOS induction was linked to NF-{kappa}B but not to JAK/STAT signaling. Interferon-{gamma} further increased the NO production by macrophages to a level that caused radiosensitization of EMT-6 cells through the bystanding effect of diffused NO. Conclusions: We demonstrate for the first time that activated macrophages may radiosensitize tumor cells through the induction of NO synthesis, which occurs in both tumor and immune cells.

Ridder, Mark de [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium)]. E-mail: Mark.De.Ridder@vub.ac.be; Verovski, Valeri N. [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Darville, Martine I. [Laboratory of Experimental Medicine, Universite Libre de Bruxelles (ULB), Brussels (Belgium); Berge, Dirk L. van den [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Monsaert, Christinne [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Eizirik, Decio L. [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Storme, Guy A. [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium)

2004-10-01

11

CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion  

Microsoft Academic Search

CD1d-restricted T cells contribute to tumor protection, but their precise roles remain unclear. Here we show that tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor induce the expansion of CD1d-restricted T cells through a mechanism that involves CD1d and macrophage inflammatory protein 2 expression by CD8-, CD11c+ dendritic cells (DCs). The antitumor immunity stimulated by vaccination with irradiated, granulocyte-macrophage colony-stimulating

Silke Gillessen; Yuri N. Naumov; Edward E. S. Nieuwenhuis; Mark A. Exley; Frederick S. Lee; Nicolas Mach; Andrew D. Luster; Richard S. Blumberg; Masaru Taniguchi; Steven P. Balk; Jack L. Strominger; Glenn Dranoff; S. Brian Wilson

2003-01-01

12

Some Biochemical Aspects of the Immune Macrophage  

PubMed Central

Some of the biochemical properties of mouse peritoneal macrophages immune to Corynebacterium ovis were characterised. Total cellular protein of immune cells exceeded that of normal phagocytes by 1·85 times. The activities of 7 hydrolytic enzymes, acid phosphatase, ?-glucuronidase, Cathepsin D, lysozyme, BPN-ase, MN esterase and aryl sulphatase were measured in lysed cell suspensions and monolayer cultures. Immune macrophages possessed substantially higher levels of these enzymes than did normal cells. No one enzyme was significantly more associated with the development of cellular immunity than another. Resting immune macrophages consumed significantly less oxygen than normal cells required but were twice as active in glycolysis. ATP levels, in agreement, were 5 times higher in normal macrophages whereas ATP-ase activities were equivalent. Normal macrophages were approximately twice as active in protein synthesis measured by the in vitro incorporation of 14C L-glycine by monolayer cultures than were immune cells. These results were considered in the light of known morphological differences between the 2 cells noted at the ultrastructural level.

Hard, G. C.

1970-01-01

13

Neuroendocrine and immune interactions with airway macrophages  

Microsoft Academic Search

Immune cells, including macrophages, are sources of many cytokines as well as a number of peptide hormones such as corticotropic releasing hormone and the endorphins. These mediators are involved in local immune regulation and may also function in an endocrine manner to influence the systemic hormonal response to stress. In turn, the major effectors of the systemic stress response, namely

D. E. James; F. P. Nijkamp

2000-01-01

14

MANGANESE CHLORIDE ENHANCES NATURAL CELL-MEDIATED IMMUNE EFFECTOR CELL FUNCTION: EFFECTS ON MACROPHAGES  

EPA Science Inventory

A single intramuscular injection of MnCl2 in mice caused an increase in macrophage functional activity. Spleen cell antibody-dependent cellmediated cytotoxicity (ADCC) against both chicken erythrocytes and P815 tumor cell targets was enhanced 24 hours following a single injection...

15

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

16

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

17

B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity.  

PubMed

Neutralizing antibodies have been thought to be required for protection against acutely cytopathic viruses, such as the neurotropic vesicular stomatitis virus (VSV). Utilizing mice that possess B cells but lack antibodies, we show here that survival upon subcutaneous (s.c.) VSV challenge was independent of neutralizing antibody production or cell-mediated adaptive immunity. However, B cells were absolutely required to provide lymphotoxin (LT) ?1?2, which maintained a protective subcapsular sinus (SCS) macrophage phenotype within virus draining lymph nodes (LNs). Macrophages within the SCS of B cell-deficient LNs, or of mice that lack LT?1?2 selectively in B cells, displayed an aberrant phenotype, failed to replicate VSV, and therefore did not produce type I interferons, which were required to prevent fatal VSV invasion of intranodal nerves. Thus, although B cells are essential for survival during VSV infection, their contribution involves the provision of innate differentiation and maintenance signals to macrophages, rather than adaptive immune mechanisms. PMID:22386268

Moseman, E Ashley; Iannacone, Matteo; Bosurgi, Lidia; Tonti, Elena; Chevrier, Nicolas; Tumanov, Alexei; Fu, Yang-Xin; Hacohen, Nir; von Andrian, Ulrich H

2012-03-01

18

Avian Macrophages: Regulators of Local and Systemic Immune Responses  

Microsoft Academic Search

Macrophages are key regulatory cells of the immune system involved in initiating and directing the innate and specific immune responses, the systemic acute phase response, tissue repair, and tissue remodel- ing. In the early stages of a challenge from invading microorganisms or from tissue injury, macrophages defend local and systemic homeostasis by initiating a complex series of cellular, biochemical, and

KIRK C. KLASING

1998-01-01

19

Cooperativity between CD8+ T cells, non-neutralizing antibodies, and alveolar macrophages is important for heterosubtypic influenza virus immunity.  

PubMed

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

2013-03-14

20

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.

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

21

Macrophage migration inhibitory factor: a regulator of innate immunity  

Microsoft Academic Search

For more than a quarter of a century, macrophage migration inhibitory factor (MIF) has been a mysterious cytokine. In recent years, MIF has assumed an important role as a pivotal regulator of innate immunity. MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro-inflammatory functions of immune cells. A rapidly increasing amount

Thierry Roger; Thierry Calandra

2003-01-01

22

Bacillus cereus immune escape: a journey within macrophages.  

PubMed

During bacterial infection, professional phagocytes are attracted to the site of infection, where they constitute a first line of host cell defense. Their function is to engulf and destroy the pathogens. Thus, bacteria must withstand the bactericidal activity of professional phagocytes, including macrophages to counteract the host immune system. Bacillus cereus infections are characterized by bacteremia despite the accumulation of inflammatory cells at the site of infection. This implies that the bacteria have developed means of resisting the host immune system. Bacillus cereus spores survive, germinate, and multiply in contact with macrophages, eventually producing toxins that kill these cells. However, the exact mechanism by which B. cereus evades immune attack remains unclear. This review addresses the interaction between B. cereus and macrophages, highlighting, in particular, the ways in which the bacteria escape the microbicidal activities of professional phagocytes. PMID:23827020

Tran, Seav-Ly; Ramarao, Nalini

2013-08-13

23

Vdelta1+ gammadelta T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice.  

PubMed

An influx of neutrophils followed a short time later by an influx of macrophages to the infected site plays a key role in innate immunity against Escherichia coli infection. We found in this study that Vdelta1-/- mice exhibited impaired accumulation of peritoneal macrophages but not neutrophils and delayed bacterial clearance after i.p. inoculation with E. coli. Peritoneal gammadelta T cells from E. coli-infected wild-type mice produced CCL3/MIP-1alpha and CCL5/RANTES in response to gammadelta TCR triggering in vitro, whereas such production was not evident in gammadelta T cells from E. coli-infected Vdelta1-/- mice. Neutralization of CCL3/MIP-1alpha by a specific mAb in vivo significantly inhibited the accumulation of macrophages in the peritoneal cavity after E. coli infection, resulting in exacerbated bacterial growth in the peritoneal cavity. These results suggest that Vdelta1+ gammadelta T cells bridge a gap between neutrophils and macrophages in innate immunity during E. coli infection mediated by production of CC chemokines, enhancing macrophage trafficking to the site of infection. PMID:15470060

Tagawa, Tetsuzo; Nishimura, Hitoshi; Yajima, Toshiki; Hara, Hiromitsu; Kishihara, Kenji; Matsuzaki, Goro; Yoshino, Ichiro; Maehara, Yoshihiko; Yoshikai, Yasunobu

2004-10-15

24

A case report: Immune responses and clinical course of the first human use of granulocyte\\/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy  

Microsoft Academic Search

The first use of granulocyte\\/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells\\u000a as a therapeutic vaccine in a patient with rapidly progressive, widely disseminated malignant melanoma resulted in the generation\\u000a of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction\\u000a to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing

K. A. O. Ellem; Michael G. E. O’Rourke; Gregory R. Johnson; Gordon Parry; Ihor S. Misko; Christopher W. Schmidt; Peter G. Parsons; Scott R. Burrows; Simone Cross; Andrew Fell; Chung-Leung Li; John R. Bell; Philip J. Dubois; Denis J. Moss; Michael F. Good; Anne Kelso; Lawrence K. Cohen; Glenn Dranoff; Richard C. Mulligan

1997-01-01

25

Functional role of Akt in macrophage-mediated innate immunity.  

PubMed

Akt (protein kinase B) is a serine/threonine protein kinase that regulates cell metabolism, survival and proliferation. Recent studies of the role of Akt in phagocytosis, intracellular bacterial infections, LPS tolerance, production of inflammatory cytokines and mediators, and migration during macrophage-mediated innate immunity strongly suggest a pivotal role for this enzyme in the functional activation of macrophages. Considering that a variety of inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer and osteoporosis, are regulated by macrophage-mediated innate immunity, efforts should be more carefully focused on understanding the function of Akt in macrophage-mediated innate immunity. Although few studies have addressed this question, this review discusses recent findings that support an important role for Akt in macrophage-mediated innate immunity and underlines the need for trials to develop pharmaceutically useful drugs that target Akt for treatment of macrophage-mediated inflammatory diseases. The findings we review here suggest that a novel and safe Akt inhibitor with strong immunosuppressive and anti-inflammatory properties will be applied to various chronic inflammatory diseases in the near future. PMID:21196185

Lee, Yong Gyu; Lee, Jaehwi; Byeon, Se Eun; Yoo, Dae Sung; Kim, Min Ho; Lee, Song Yi; Cho, Jae Youl

2011-01-01

26

Study of biomaterial-induced macrophage activation, cell-mediated immune response and molecular oxidative damage in patients with dermal bioimplants  

Microsoft Academic Search

Several soft-tissue dermal fillers have been reported to provoke immunogenicity and may cause adverse reactions despite claims regarding their safety. This study aimed to assess biomaterial-induced macrophage activation, cell-mediated immune response and oxidative stress in 169 patients with dermal bioimplants. To this end, we analysed plasma concentrations of myeloperoxidase (MPO), the chitinase-like proteins chitotriosidase and YKL-40 and molecular oxidative damage.

Olga Sánchez; Víctor Rodríguez-Sureda; Carmen Domínguez; Teresa Fernández-Figueras; Angel Vilches; Elisa Llurba; Jaume Alijotas-Reig

27

Exosomes isolated from mycobacteria-infected mice or cultured macrophages can recruit and activate immune cells in vitro and in vivo  

PubMed Central

Over 2 billion people are infected with M. tuberculosis (M.tb); however, only 5–10% of those infected will develop active disease. Recent data suggest that containment is controlled locally at the level of the granuloma and that granuloma architecture may differ even within a single infected individual. Formation of a granuloma likely requires exposure to mycobacterial components released from infected macrophages but the mechanism of their release is still unclear. We hypothesize that exosomes, which are small membrane vesicles containing mycobacterial components released from infected macrophages, could promote cellular recruitment during granuloma formation. In support of this hypothesis, we found that C57BL/6 mouse-derived bone marrow macrophages treated with exosomes released from M.tb-infected RAW264.7 cells secrete significant levels of chemokines and can induce migration of CFSE-labeled macrophages and splenocytes. Exosomes isolated from the serum of M. bovis BCG infected mice could also stimulate macrophage production of chemokines and cytokines ex vivo but the level and type differed during the course of a 60 day infection. Interestingly, the exosome concentration in serum correlated strongly with mouse bacterial load, suggesting some role in immune regulation. Finally, hollow fiber-based experiments indicated that macrophages treated with exosomes released from Mtb-infected cells could promote macrophage recruitment in vivo. Exosomes injected intranasally could also recruit CD11b+ cells into the lung. Overall, our study suggests that exosomes may play an important role in recruiting and regulating host cells during an M. tuberculosis infection.

Singh, Prachi P.; Smith, Victoria L.; Karakousis, Petros C.; Schorey, Jeffery S.

2013-01-01

28

Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans.  

PubMed

Autophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. We evaluated the role of macrophage autophagy in the response to Cryptococcus neoformans and Candida albicans, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing C. albicans. In contrast, LC3 was found in only a few vacuoles containing C. neoformans previously opsonized with antibody but never after complement-mediated phagocytosis. Disruption of host autophagy in vitro by RNA interference against ATG5 (autophagy-related 5) decreased the phagocytosis of C. albicans and the fungistatic activity of J774.16 macrophage-like cells against both fungi, independent of the opsonin used. ATG5-knockout bone marrow-derived macrophages (BMMs) also had decreased fungistatic activity against C. neoformans when activated. In contrast, nonactivated ATG5-knockout BMMs actually restricted C. neoformans growth more efficiently, suggesting that macrophage autophagy plays different roles against C. neoformans, depending on the macrophage type and activation. Interference with autophagy in J774.16 cells also decreased nonlytic exocytosis of C. neoformans, increased interleukin-6 secretion, and decreased gamma interferon-induced protein 10 secretion. Mice with a conditionally knocked out ATG5 gene in myeloid cells showed increased susceptibility to intravenous C. albicans infection. In contrast, these mice manifested no increased susceptibility to C. neoformans, as measured by survival, but had fewer alternatively activated macrophages and less inflammation in the lungs after intratracheal infection than control mice. These results demonstrate the complex roles of macrophage autophagy in restricting intracellular parasitism by fungi and reveal connections with nonlytic exocytosis, humoral immunity, and cytokine signaling. PMID:22710871

Nicola, André Moraes; Albuquerque, Patrícia; Martinez, Luis R; Dal-Rosso, Rafael Antonio; Saylor, Carolyn; De Jesus, Magdia; Nosanchuk, Joshua D; Casadevall, Arturo

2012-06-18

29

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

PubMed

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 13 cytokines and chemokines are produced within 4 h of injection including IL-1beta and IL-5. Optimal production of some of these, including IL-1beta, depends upon both macrophages and mast cells, whereas 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, Ab 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-1beta. Furthermore, endogenous CD4 and CD8 T cell responses, Ab 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 adjuvant effect of alum 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

2009-09-04

30

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...

31

Impact of macrophage and dendritic cell subset elimination on antiviral immunity, viral clearance and production of type 1 interferon  

Microsoft Academic Search

We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper 1) and Th2 cytokine response detectable ex vivo. Liposome-encapsulated clodronate-mediated elimination of CD8? marginal dendritic cells (DCs) and splenic macrophages (m?), but not CD8+ interdigitating DCs, prior to infection resulted in a markedly diminished chemokine and Th1 (IL-2, interferon-?) cytokine response, although the Th2 response

Richard P. Ciavarra; Lisa Taylor; Amy R. Greene; Nazita Yousefieh; Dale Horeth; Nico van Rooijen; Christina Steel; Betsy Gregory; Mark Birkenbach; Margaret Sekellick

2005-01-01

32

Innate immunity and monocyte-macrophage activation in atherosclerosis  

PubMed Central

Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.

2011-01-01

33

Regulation of macrophage immune responses by antipsychotic drugs.  

PubMed

Abstract Antipsychotic drugs (APDs) have been used to ease clinical psychotic symptoms. APDs have also been recently discovered to induce immune regulation. Our previous studies found that atypical APDs risperidone and clozapine could inhibit INF-? production of human peripheral blood mononuclear cells (PBMC) and could inhibit Th1 differentiation. This study further investigates APD effects on monocyte-derived macrophages, which are the major antigen-presenting cells in PBMC. Our data suggest that adhesion, phagocytosis and reactive oxygen species production of monocytic cell lines would be inhibited by haloperidol, risperidone or clozapine. Also, that APDs inhibited the production of LPS-stimulated macrophages IL-6 and IL-8 suggests that risperidone and clozapine may inhibit inflammation. We further discovered that risperidone and clozapine could inhibit IL-12 production and increase IL-10 production of LPS-stimulated macrophages. These results indicated that risperidone and clozapine could inhibit Th1 differentiation not only by increasing INF-? production of PBMC but by inhibiting the release of Th1-inducing cytokines and increasing Th2-inducing cytokines of LPS-stimulated macrophages to modulate and regulate immune responses. PMID:23981042

Chen, Mao-Liang; Wu, Semon; Tsai, Tzung-Chieh; Wang, Lu-Kai; Tsai, Fu-Ming

2013-08-28

34

Monocytes, Dendritic Cells, Macrophages, T cells and Head and Neck Cancer : the effect of a thymic hormone preparation in restoring defective immune functions  

Microsoft Academic Search

It is generally accepted that cell mediated immunity (CMI) has more importance\\u000ain the control of cancer than the antibody-mediated immune response. The cell\\u000amediated immune response is the basis of the so-called natural host resistance\\u000ato cancer, which is also referred to as \\

J. D. F. Kerrebijn

1998-01-01

35

Macrophage Migration Inhibitory Factor is a Critical Mediator of the Activation of Immune Cells by Exotoxins of Gram-Positive Bacteria  

Microsoft Academic Search

Discovered in the early 1960s as a T cell cytokine, the protein mediator known as macrophage migration inhibitory factor (MIF) has been found recently to be a pituitary peptide released during the physiological stress response, a proinflammatory macrophage cytokine secreted after LPS stimulation, and a T cell product expressed as part of the antigen-dependent activation response. We report herein that

Thierry Calandra; Lori A. Spiegel; Christine N. Metz; Richard Bucala

1998-01-01

36

Macrophage Colony-Forming Cell.  

National Technical Information Service (NTIS)

This section will deal with the culture technique, growth characteristics, and properties of the M-CFC(Macrophage Colony Forming Cell) a CFC distinct in many ways from the more primitive GM(Granulocyte Macrophage)-CFC and HPP(Hematopoietic Progenitor Cell...

T. J. MacVittie

1984-01-01

37

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

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

1993-01-01

38

Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features  

Microsoft Academic Search

The classical T cell cytokine macrophage migration inhibitory factor (MIF) has reemerged recently as a critical mediator\\u000a of the host immune and stress response. MIF has been found to be a mediator of several diseases including gram-negative septic\\u000a shock and delayed-type hypersensitivity reactions. Its immunological functions include the modulation of the host macrophage\\u000a and T and B cell response. In

Jürgen Bernhagen; Thierry Calandra; Richard Bucala

1998-01-01

39

Transcriptional profiling of immune genes in bovine monocyte-derived macrophages exposed to bacterial antigens  

Microsoft Academic Search

The involvement of Toll-like receptors (TLRs) and other immune signalling genes during challenge of bovine macrophages with bacterial products derived from disease-causing bacteria in cattle was investigated. An in vitro cell culture model of bovine monocyte derived macrophages (MDM) was established and these cells were exposed to purified protein derivative (PPD-b) derived from Mycobacterium bovis and to lipopolysachharide (LPS) derived

Maria Taraktsoglou; Urszula Szalabska; David A. Magee; John A. Browne; Torres Sweeney; Eamonn Gormley; David E. MacHugh

2011-01-01

40

Immunity to Schistosoma mansoni in guinea-pigs vaccinated with radiation-attenuated cercariae. T-cell activation of macrophages for larval killing.  

PubMed Central

This study addresses macrophage activation in guinea-pigs vaccinated with radiation-attenuated cercariae of Schistosoma mansoni. Peritoneal exudate macrophages elicited in vaccinated animals by mineral oil injection were activated to kill larval schistosomes in vitro. Killing efficiency is dependent upon the cell: target ratio employed and is enhanced by, but is not strictly dependent on, the presence of specific antibodies. Macrophages co-cultured with parasites release superoxide radicals and hydrogen peroxide, but the use of inhibitors has shown that neither of these reactive oxygen intermediates are the causal agents of cellular cytotoxicity in this system. Oil-elicited macrophages from naive guinea-pigs do not show comparable activation; they can, however, be activated in vitro by incubation with culture supernatant fluids from schistosome antigen-stimulated spleen, or lymph node cells harvested from vaccinated guinea-pigs. Naive macrophages activated in this way kill schistosomula in vitro and release the activation markers IL-1 and superoxide anion. The macrophage-activating factor (MAF) present in spleen cell culture supernatant fluids has a MW of 35,000-55,000, but does not have the chemical characteristics of gamma-interferon. In this study MAF is shown to be released by a population of lymph node cells that does not adhere to nylon-wool columns, that responds well in proliferation assays to schistosome antigens and to the T-cell mitogen concanavalin A, but does not respond to the B-cell mitogen lipopolysaccharide. These cells have been identified as small lymphocytes.

Gordon, J R; McLaren, D J

1988-01-01

41

Dendritic cells and macrophages in the genitourinary tract  

Microsoft Academic Search

Dendritic cells (DCs) and macrophages are antigen-presenting cells (APCs) that are important in innate immune defense as well as in the generation and regulation of adaptive immunity against a wide array of pathogens. The genitourinary (GU) tract, which serves an important reproductive function, is constantly exposed to numerous agents of sexually transmitted infections (STIs). To combat these STIs, several subsets

N Iijima; J M Thompson; A Iwasaki

2008-01-01

42

A second combinatorial immune receptor in monocytes/macrophages is based on the TCR??.  

PubMed

Recent evidence indicates that monocytes and macrophages express T cell receptor (TCR)??-like combinatorial immune receptors. Here, we demonstrate the presence of a second recombinatorial immunoreceptor, which is structurally based on the TCR ?- and ?-chains, in human and murine monocytes and differentially activated macrophages (referred to here as TCRL(m)??). In vitro, infection of macrophages with mycobacteria and gram positive or gram negative bacteria induced expression of donor-specific and differential TCRL(m)V? repertoires indicating that the novel immunoreceptor represents a dynamic flexible host defense system that responds to bacterial challenge. In vivo, we find that TCRL(m)?? bearing macrophages, which express highly restricted repertoires of the antigen-binding V? chain, accumulate in the cerebrospinal fluid in acute bacterial meningitis and in advanced lesions of atherosclerosis. These results identify an as yet unrecognized monocyte/macrophage subpopulation that bears combinatorial TCRL(m)?? immune receptors, and is associated with both acute and chronic inflammatory diseases. Moreover, they indicate that the monocytic lineage uses the same bipartite system of TCR??/TCR??-based combinatorial immune receptors that is present in T cells. Our findings suggest specific roles of monocytes/macrophages in various inflammatory conditions and lend further evidence that flexible immune recognition in higher vertebrates operates on a broader cellular basis than previously thought. PMID:23312956

Fuchs, Tina; Puellmann, Kerstin; Hahn, Martin; Dollt, Claudia; Pechlivanidou, Ioanna; Ovsiy, Ilja; Kzhyshkowska, Julia; Gratchev, Alexei; Fleig, Julian; Emmert, Alexander; Neumaier, Michael; Beham, Alexander W; Kaminski, Wolfgang E

2012-11-26

43

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

2013-05-10

44

Expression of oestrogen and progesterone receptors by mast cells alone, but not lymphocytes, macrophages or other immune cells in human upper airways  

Microsoft Academic Search

BACKGROUNDNasal polyposis often coexists with asthma in airway inflammatory conditions characterised by the infiltration of a range of immune cells. A potentially important role for ovarian hormones has been implicated in airway inflammation but the cellular target for such action is not known.METHODSExpression of oestrogen receptors (ER) and progesterone receptors (PR) was examined using immunohistochemistry in formalin fixed nasal polyp

X J Zhao; G McKerr; Z Dong; C A Higgins; J Carson; Z Q Yang; B M Hannigan

2001-01-01

45

Innate and adaptive immune response to apoptotic cells  

Microsoft Academic Search

The immune system is constantly exposed to dying cells, most of which arise during central tolerance and from effete circulating immune cells. Under homeostatic conditions, phagocytes (predominantly macrophages and dendritic cells) belonging to the innate immune system, rapidly ingest cells and their debris. Apoptotic cell removal requires recognition of altered self on the apoptotic membrane, a process which is facilitated

YuFeng Peng; David A. Martin; Justin Kenkel; Kang Zhang; Carol Anne Ogden; Keith B. Elkon

2007-01-01

46

Unique Proteomic Signatures Distinguish Macrophages and Dendritic Cells  

PubMed Central

Monocytes differentiate into heterogeneous populations of tissue macrophages and dendritic cells (DCs) that regulate inflammation and immunity. Identifying specific populations of myeloid cells in vivo is problematic, however, because only a limited number of proteins have been used to assign cellular phenotype. Using mass spectrometry and bone marrow-derived cells, we provided a global view of the proteomes of M-CSF-derived macrophages, classically and alternatively activated macrophages, and GM-CSF-derived DCs. Remarkably, the expression levels of half the plasma membrane proteins differed significantly in the various populations of cells derived in vitro. Moreover, the membrane proteomes of macrophages and DCs were more distinct than those of classically and alternatively activated macrophages. Hierarchical cluster and dual statistical analyses demonstrated that each cell type exhibited a robust proteomic signature that was unique. To interrogate the phenotype of myeloid cells in vivo, we subjected elicited peritoneal macrophages harvested from wild-type and GM-CSF-deficient mice to mass spectrometric and functional analysis. Unexpectedly, we found that peritoneal macrophages exhibited many features of the DCs generated in vitro. These findings demonstrate that global analysis of the membrane proteome can help define immune cell phenotypes in vivo.

Becker, Lev; Liu, Ning-Chun; Averill, Michelle M.; Yuan, Wei; Pamir, Nathalie; Peng, Yufeng; Irwin, Angela D.; Fu, Xiaoyun; Bornfeldt, Karin E.; Heinecke, Jay W.

2012-01-01

47

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

PubMed Central

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.

Abu Khweek, Arwa; Fernandez Davila, 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

48

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

2013-05-27

49

WORLD'S POULTRY SCIENCE ASSOCIATION INVITED LECTURE Avian Macrophage and Immune Response: An Overview1  

Microsoft Academic Search

Macrophages belong to the mononuclear phagocytic system lineage. This cell type is unique in that it is a crucial player in both the innate and adaptive immune responses. The material described in this over- view is a brief description of what I presented as a World's Poultry Science Association-sponsored lecture at the an-

M. A. Qureshi

50

Loss of PPAR gamma in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue.  

PubMed

Abscisic acid (ABA) is a natural phytohormone and peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that significantly improves insulin sensitivity in db/db mice. Although it has become clear that obesity is associated with macrophage infiltration into white adipose tissue (WAT), the phenotype of adipose tissue macrophages (ATMs) and the mechanisms by which insulin-sensitizing compounds modulate their infiltration remain unknown. We used a loss-of-function approach to investigate whether ABA ameliorates insulin resistance through a mechanism dependent on immune cell PPARgamma. We characterized two phenotypically distinct ATM subsets in db/db mice based on their surface expression of F4/80. F4/80(hi) ATMs were more abundant and expressed greater concentrations of chemokine receptor (CCR) 2 and CCR5 when compared to F4/80(lo) ATMs. ABA significantly decreased CCR2(+) F4/80(hi) infiltration into WAT and suppressed monocyte chemoattractant protein-1 (MCP-1) expression in WAT and plasma. Furthermore, the deficiency of PPARgamma in immune cells, including macrophages, impaired the ability of ABA to suppress the infiltration of F4/80(hi) ATMs into WAT, to repress WAT MCP-1 expression and to improve glucose tolerance. We provide molecular evidence in vivo demonstrating that ABA improves insulin sensitivity and obesity-related inflammation by inhibiting MCP-1 expression and F4/80(hi) ATM infiltration through a PPARgamma-dependent mechanism. PMID:17618105

Guri, Amir J; Hontecillas, Raquel; Ferrer, Gerardo; Casagran, Oriol; Wankhade, Umesh; Noble, Alexis M; Eizirik, Decio L; Ortis, Fernanda; Cnop, Miriam; Liu, Dongmin; Si, Hongwei; Bassaganya-Riera, Josep

2007-07-06

51

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

PubMed

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. PMID:23954561

Srivastava, Ritesh K; Li, Changzhao; Chaudhary, Sandeep C; Ballestas, Mary E; Elmets, Craig A; Robbins, David J; Matalon, Sadis; Deshane, Jessy S; Afaq, Farrukh; Bickers, David R; Athar, Mohammad

2013-08-14

52

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

53

Immune Evasion by Helicobacter pylori is Mediated by Induction of Macrophage Arginase II1  

PubMed Central

Helicobacter pylori infection persists for the life of the host due to the failure of the immune response to eradicate the bacterium. Determining how H. pylori escapes the immune response in its gastric niche is clinically important. We have demonstrated in vitro that macrophage NO production can kill H. pylori, but induction of macrophage arginase II (Arg2) inhibits inducible NO synthase (iNOS) translation, causes apoptosis, and restricts bacterial killing. We now determined if Arg2 impairs host defense in vivo, using a chronic H. pylori infection model. In C57BL/6 mice, expression of Arg2, but not arginase I (Arg1), was abundant and localized to gastric macrophages. Arg2?/? mice had increased histologic gastritis and decreased bacterial colonization compared to wild-type (WT) mice. Increased gastritis scores correlated with decreased colonization in individual Arg2?/? mice, but not WT mice. When mice infected with H. pylori were compared, Arg2?/? mice had more gastric macrophages, more of these cells were iNOS+, and these cells expressed higher levels of iNOS protein, as determined by flow cytometry and immunofluorescence microscopy. There was enhanced nitrotyrosine staining in infected Arg2?/? versus WT mice, indicating increased NO generation. Infected Arg2?/? mice exhibited decreased macrophage apoptosis, as well as enhanced IFN-?, IL-17a, and IL-12p40 expression, and reduced IL-10 levels consistent with a more vigorous Th1/Th17 response. These studies demonstrate that Arg2 contributes to the immune evasion of H. pylori by limiting macrophage iNOS protein expression and NO production, mediating macrophage apoptosis, and restraining pro-inflammatory cytokine responses.

Lewis, Nuruddeen D.; Asim, Mohammad; Barry, Daniel P.; de Sablet, Thibaut; Singh, Kshipra; Piazuelo, Maria B.; Gobert, Alain P.; Chaturvedi, Rupesh; Wilson, Keith T.

2011-01-01

54

Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease 1 1 This review is written to mark the retirement of Prof. Eric A. Newsholme, University of Oxford, United Kingdom, and to acknowledge his contribution to the field of immune cell metabolism  

Microsoft Academic Search

Many aspects of the cell biology of lymphocytes, macrophages, and neutrophils have been studied extensively. Our recent work on these cells has investigated how fuel metabolism, especially glutamine metabolism, is related to the specific function of these cells in the inflammatory response. The high rate of glutamine utilization and its metabolism in such immune cells has raised the question of

P. Newsholme; R. Curi; T. C. Pithon Curi; C. J. Murphy; C. Garcia; M. Pires de Melo

1999-01-01

55

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

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

1995-01-01

56

Helicobacter pylori Infection Is Associated with Increased Expression of Macrophage Migratory Inhibitory Factor—by Epithelial Cells, T Cells, and Macrophages—in Gastric Mucosa  

Microsoft Academic Search

The macrophage migratory inhibitory factor (MIF) plays a pivotal role in inflammatory and immune diseases; however, its role in gastrointestinal diseases has not been clarified. This study intended to determine the expression of MIF, by gastric epithelial cells, T cells, and macrophages, in Helicobacter pylori-induced gastritis. Sixty-four patients (30 males, 34 females; mean age, 47 years) referred for upper endoscopy

2004-01-01

57

Macrophages, Dendritic cells and Kidney Ischemia-Reperfusion Injury  

PubMed Central

Dendritic cells and macrophages are critical early initiators of innate immunity in the kidney and orchestrate inflammation subsequent to ischemia-reperfusion injury. They are the most abundant leukocyte present in the kidney, and they represent a heterogeneous population of cells that are capable of inducing ‘sterile’ inflammation following reperfusion directly through the production of proinflammatory cytokines and other soluble inflammatory mediators or indirectly through activation of effector T lymphocytes and nature killer T cells. In addition, recent studies indicate that kidney and immune cell microRNAs control gene expression and have the ability to regulate the initial inflammatory response to injury. Although dendritic cells and macrophages contribute to both innate and adaptive immunity and to injury and repair, this review will focus on the initial innate response to kidney ischemia-reperfusion injury.

Li, Li; Okusa, Mark D.

2010-01-01

58

Cell interactions in the initial contact between cultured melanoma cells and syngeneic macrophages.  

PubMed Central

Thioglycolate-induces peritoneal macrophages from melanoma-bearing mice (immune macrophages) or from control mice (control macrophages) were cultured with syngeneic melanoma cells (P51) to determine the surface characteristics of the effector cells during interaction and destruction of the target cells. After a short culture period (3 hours), immune macrophages had extensive connections via filopodia and ruffled membranes to the surfaces of the melanoma cells; control macrophages did not exhibit the same behavior. A dense region in the cytoplasm immediately beneath the macrophage plasmalemma was observed at the point of contact with the target tumor cell. With longer periods of culture (24 hours), effector cells began phagocytosis of the target cells; immune macrophages, however, had more fine filopodial connections and were more cytostatic than were controls. These observations indicate that one of the initial mechanisms of tumor cell destruction was contact-induced lysis, with phagocytosis playing a minor part. Images Figure 5 Figure 6 Figure 7 Figure 8 Figure 1 Figure 2 Figure 3 Figure 4 Figure 9 Figure 10

Erickson, K. L.; Hu, F.

1979-01-01

59

Macrophages.com: an on-line community resource for innate immunity research.  

PubMed

Macrophages play a major role in tissue remodelling during development, wound healing and tissue homeostasis, and are central to innate immunity and to the pathology of tissue injury and inflammation. Given this fundamental role in many aspects of biological function, an enormous wealth of information has accumulated on these fascinating cells in the literature and other public repositories. With the escalation of genome-scale data derived from macrophages and related haematopoietic cell types, there is a growing need for an integrated resource that seeks to compile, organise and analyse our collective knowledge of macrophage biology. Here we describe a community-driven web-based resource, macrophages.com that aims to provide a portal onto various types of Omics data to facilitate comparative genomic studies, promoter and transcriptional network analyses, models of macrophage pathways together with other information on these cells. To this end, the website combines public and in-house analyses of expression data with pre-analysed views of co-expressed genes as supported by the network analysis tool BioLayout Express(3D), as well as providing access to maps of pathways active in macrophages. Macrophages.com also provides access to an extensive image library of macrophages in adult/embryonic tissue sections prepared from normal and transgenic mice. In addition, the site links to the Human Protein Atlas database so as to provide direct access to protein expression patterns in human macrophages. Finally, an integrated gene-centric portal provides the tools for rapid promoter analysis studies based on a comprehensive set of CAGE-derived transcription start site (TSS) sequences in human and mouse genomes as generated by the Functional Annotation of Mammalian genomes (FANTOM) projects initiated by the RIKEN Omics Science Center. Our aim is to continue to grow the macrophages.com resource using publicly available data, as well as in-house generated knowledge. In so doing we aim to provide a user-friendly community website and a community portal for access to comprehensive sets of macrophage-related data. PMID:21924793

Robert, Christelle; Lu, Xiang; Law, Andrew; Freeman, Tom C; Hume, David A

2011-07-23

60

Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes  

PubMed Central

A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fc?-receptor signalling. The activation of Fc? receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fc? receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fc? receptors by infectious immune complexes.

Halstead, Scott B; Mahalingam, Prof Suresh; Marovich, Mary A; Ubol, Sukathida; Mosser, Prof David M

2011-01-01

61

Immune modulatory effects of Prunella vulgaris L. on monocytes/macrophages.  

PubMed

Prunella vulgaris L. (Labiatae), a popular Western and Chinese herbal medicine, has long been associated with anti-viral and anti-bacterial effects. While its anti-viral effects are attributed mainly to the inhibition of virus replication, the biological mechanisms of its anti-bacterial effects remain unknown. As a biological response modifier (BRM), the polysaccharides isolated from P. vulgaris have been shown to up-regulate the immune responses of monocytes/macrophages. However, the immune stimulatory effects seem to contradict its well-known anti-inflammatory properties. We hypothesized that the anti-microbial effects exhibited by the polysaccharides isolated from P. vulgaris encompass both anti-inflammatory and immune stimulatory effects. One of the polysaccharide fractions PV2IV markedly stimulated the production of superoxide and nitrite representing nitric oxide from murine macrophage RAW264.7 and brain macrophage BV2 cells. The amount of nitrite and superoxide produced after PV2IV stimulation was as high as that stimulated by bacterial endotoxin lipopolysaccharide (LPS) in a dose-dependent manner. In addition, PV2IV also increased cellular protein levels of inducible nitric oxide synthase (iNOS) and mRNA for tumor necrosis factor-alpha (TNFalpha). Similar to the effects of a high dose of LPS, the fraction PV2 could trigger activation-induced cell death (AICD) by stimulating caspase-3 activity and reduction of MTT uptake in monocytes/macrophages. These results may help our understanding of the molecular mechanism of P. vulgaris, which exhibited both immune stimulatory and anti-inflammatory effects against microbial invasion. PMID:16273294

Fang, Xuya; Yu, Mabel Man-Shan; Yuen, Wai-Hung; Zee, Sze Yong; Chang, Raymond Chuen-Chung

2005-12-01

62

Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival.  

National Technical Information Service (NTIS)

Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contrib...

W. J. Ribot R. G. Panchal K. C. Brittingham G. Ruthel T. A. Kenny

2006-01-01

63

Gastric Sonic Hedgehog Acts as a Macrophage Chemoattractant During the Immune Response to Helicobacter pylori  

PubMed Central

Background & Aims Macrophages mediate the epithelial response to Helicobacter pylori and are involved in the development of gastritis. Sonic Hedgehog (Shh) regulates gastric epithelial differentiation and function, but little is known about its immunoregulatory role in the stomach. We investigated whether gastric Shh acts as a macrophage chemoattractant during the innate immune response to H pylori infection. Methods Mice with parietal cell-specific deletion of Shh (PC-ShhKO) and control mice were infected with H pylori. Levels of gastric Shh, cytokines, and chemokines were assayed by quantitative reverse-transcriptase PCR or by a Luminex®-based multiplex assay, 2, 7, or 180 days after infection. Circulating concentrations of Shh were measured by ELISA. Bone marrow chimera experiments were performed with mice that have myeloid cell-specific deletion of the Hedgehog signal transduction protein smoothened (LysMCre/SmoKO). Macrophage recruitment was measured in gastric tissue and peripheral blood by fluorescence-activated cell sorting analysis. Results Control mice infected with H pylori for 6 months developed an inflammatory response characterized by infiltration of CD4+ T cells and increased levels of interferon-? and interleukin (IL)-1? in the stomach. PC-ShhKO mice did not develop gastritis, even after 6 months of infection with H pylori. Control mice had increased concentrations of Shh, accompanied by the recruitment of CD11b+F4/80+Ly6Chigh macrophages 2 days after infection. Control mice that received bone marrow transplants from control mice had an influx of macrophages to the gastric mucosa in response to H pylori infection; this was not observed in H pylori-infected control mice that received bone marrow transplants from LysMCre/SmoKO mice. Conclusion H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.

Schumacher, Michael A.; Donnelly, Jessica M.; Engevik, Amy C.; Xiao, Chang; Yang, Li; Kenny, Susan; Varro, Andrea; Hollande, Frederic; Samuelson, Linda C.; Zavros, Yana

2012-01-01

64

Immune-to-brain signalling: the role of cerebral CD163-positive macrophages.  

PubMed

Systemic inflammation induces cytokine synthesis within the central nervous system. This results in sickness behaviour and may exacerbate ongoing neuroinflammatory disease. The precise mechanisms underlying the relay of signal from the periphery to the central nervous system are not entirely understood. CD163-positive macrophages occupy a unique position at the blood-brain barrier and upregulate prostaglandin-synthesizing enzymes in response to systemic inflammation. This finding suggests that they might play a role in signalling inflammation to the central nervous system. However, here we demonstrate that de novo brain cytokine transcription during systemic endotoxaemia may be prostaglandin-independent. We therefore set out to interrogate more directly the role of CD163-positive macrophages in immune-to-brain signalling. Intracerebroventricular injections of clodronate liposomes were used to selectively deplete CD163-positive macrophages. We show that de novo brain cytokine synthesis during systemic endotoxaemia persists in the absence of CD163-positive macrophages. Cerebral endothelial cells outnumber CD163-positive macrophages and are arguably better situated to signal circulating inflammatory stimuli to the brain. PMID:18852025

Galea, Ian; Felton, Leigh M; Waters, Sara; van Rooijen, Nico; Perry, V Hugh; Newman, Tracey A

2008-10-05

65

Macrophage Expression of HIF-1? Suppresses T cell Function and Promotes Tumor Progression  

PubMed Central

T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their impact on tumor progression is poorly understood. Targeted deletion of the hypoxia responsive transcription factor HIF-1? in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although VEGF-A and vascularization was unchanged. Tumor associated macrophages can suppress tumor infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T cell suppression in vitro in a manner dependent on macrophage expression of HIF-1?. Our findings link the innate immune hypoxic response to tumor progression through induction of T cell suppression in the tumor microenvironment.

Doedens, Andrew L.; Stockmann, Christian; Rubinstein, Mark P.; Liao, Debbie; Zhang, Na; DeNardo, David G.; Coussens, Lisa M.; Karin, Michael; Goldrath, Ananda W.; Johnson, Randall S.

2010-01-01

66

To Study the Effect of Paclitaxel on the Cytoplasmic Viscosity of Murine Macrophage Immune Cell RAW 264.7 Using Self-Developed Optical Tweezers System  

NASA Astrophysics Data System (ADS)

In recent years, optical tweezers have become one of the tools to measure the mechanical properties of living cells. In this study, we first constructed an optical tweezers to investigate the cytoplasmic viscosity of immune cells. In addition to measuring viscosity of cells in a normal condition, we also treated cells with anti-cancer drug, Paclitaxel, and in order to study its effect on the cytoplasmic viscosity. The results showed that the viscosity decreased dramatically during the first 3 h. After 3 h, the change started to slow down and it remained nearly flat by the end of the experiment. In addition, we used the confocal laser scanning microscope to observe the cytoskeleton of the cell after drug treatment for 3 and 5 h, respectively, and found that actin filaments were disrupted and that the nucleus had disintegrated in some drug-treated cells, similar to the process of apoptosis. This study presents a new way for measuring the changes in cytoplasmic viscosity, and to determine if a cell is going into apoptosis as a result of a drug treatment.

Chen, Ying-chun; Wu, Chien-ming

2012-12-01

67

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

68

A critical role for alveolar macrophages in elicitation of pulmonary immune fibrosis  

PubMed Central

Hapten immune pulmonary interstitial fibrosis (HIPIF) is induced by a recall cell-mediated immune response against the hapten 2,4,6-trinitrobenzene sulphonic acid (TNBS) in the lung. Studies here dissect the role of the cellular components of the bronchoalveolar lavage (BAL) cells (alveolar macrophages [AMs] versus monocytes and immature dendritic cells) in the fibrogenic inflammatory response. BAL cells from HIPIF mice were generally more activated and produced a greater amount of tumour necrosis factor-? (TNF-?) than controls. Liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP) that was inoculated intranasally (i.n.) into mice selectively depleted AMs. Following AM depletion, the number of TNF-?-containing cells was reduced, and both the number of immune inflammatory cells recruited into the alveolar space and the subsequent collagen deposition (hydroxyproline) were decreased in the sensitized and intratracheally (i.t.) challenged mice. In conclusion, AMs are required, in part, for the development of pulmonary fibrosis in HIPIF because AM-derived factors such as TNF-? are needed for initiation of chemokine and cytokine pathways and accumulation of immune inflammatory cells.

Zhang-Hoover, J; Sutton, A; van Rooijen, N; Stein-Streilein, J

2000-01-01

69

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 MarylandÃÂs 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

70

Role of Mincle in alveolar macrophage-dependent innate immunity against mycobacterial infections in mice.  

PubMed

The role of macrophage-inducible C-type lectin Mincle in lung innate immunity against mycobacterial infection is incompletely defined. In this study, we show that wild-type (WT) mice responded with a delayed Mincle induction on resident alveolar macrophages and newly immigrating exudate macrophages to infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG), peaking by days 14-21 posttreatment. As compared with WT mice, Mincle knockout (KO) mice exhibited decreased proinflammatory mediator responses and leukocyte recruitment upon M. bovis BCG challenge, and they demonstrated increased mycobacterial loads in pulmonary and extrapulmonary organ systems. Secondary mycobacterial infection on day 14 after primary BCG challenge led to increased cytokine gene expression in sorted alveolar macrophages of WT mice, but not Mincle KO mice, resulting in substantially reduced alveolar neutrophil recruitment and increased mycobacterial loads in the lungs of Mincle KO mice. Collectively, these data show that WT mice respond with a relatively late Mincle expression on lung sentinel cells to M. bovis BCG infection. Moreover, M. bovis BCG-induced upregulation of C-type lectin Mincle on professional phagocytes critically shapes antimycobacterial responses in both pulmonary and extrapulmonary organ systems of mice, which may be important for elucidating the role of Mincle in the control of mycobacterial dissemination in mice. PMID:22869905

Behler, Friederike; Steinwede, Kathrin; Balboa, Luciana; Ueberberg, Bianca; Maus, Regina; Kirchhof, Gabriele; Yamasaki, Sho; Welte, Tobias; Maus, Ulrich A

2012-08-06

71

Sterols and oxysterols in immune cell function.  

PubMed

Intermediates in the cholesterol-biosynthetic pathway and oxysterol derivatives of cholesterol regulate diverse cellular processes. Recent studies have expanded the appreciation of their roles in controlling the functions of cells of the innate and adaptive immune systems. Here we review recent literature reporting on the biological functions of sterol intermediates and oxysterols, acting through transcription factors such as the liver X receptors (LXRs), sterol regulatory element-binding proteins (SREBPs) and the G protein-coupled receptor EBI2, in regulating the differentiation and population expansion of cells of the innate and adaptive immune systems, their responses to inflammatory mediators, their effects on the phagocytic functions of macrophages and their effects on antiviral activities and the migration of immune cells. Such findings have raised many new questions about the production of endogenous bioactive sterols and oxysterols and their mechanisms of action in the immune system. PMID:23959186

Spann, Nathanael J; Glass, Christopher K

2013-08-20

72

Electroporation and DNA-dependent cell death in murine macrophages  

Microsoft Academic Search

The difficulty of transfecting primary macrophages and macrophage ceil lines has meant that relatively few studies on regulation of gene expression have been performed in these cells. This study has optimized an electroporation procedure for the macrophage cell line RAW 264, but shows that introduction of DNA into the cytoplasm of primary macrophages by electroporation is toxic to the cells.

Katryn J Stacey; Ian L Ross; David A Hume

1993-01-01

73

IL-33 reduces macrophage foam cell formation.  

PubMed

The development of atherosclerosis, a chronic inflammatory disease characterized by the formation of arterial fibrotic plaques, has been shown to be reduced by IL-33 in vivo. However, whether IL-33 can directly affect macrophage foam cell formation, a key feature of atherosclerotic plaques, has not been determined. In this study, we investigated whether IL-33 reduces macrophage foam cell accumulation in vivo and if IL-33 reduces their formation in vitro using THP-1 and primary human monocyte-derived macrophages. In Apolipoprotein E(-/-) mice fed on a high fat diet, IL-33 treatment significantly reduced the accumulation of macrophage-derived foam cells in atherosclerotic plaques. IL-33 also reduced macrophage foam cell formation in vitro by decreasing acetylated and oxidized low-density lipoprotein uptake, reducing intracellular total and esterified cholesterol content and enhancing cholesterol efflux. These changes were associated with IL-33-mediated reduction in the expression of genes involved in modified low-density lipoprotein uptake, such as CD36, and simultaneous increase in genes involved in cholesterol efflux, including Apolipoprotein E, thereby providing a mechanism for such an action for this cytokine. IL-33 also decreased the expression of key genes implicated in cholesterol esterification and triglyceride storage, including Acyl-CoA:cholesterol acyltransferase 1 and Adipocyte differentiation-related protein. Furthermore, using bone marrow-derived macrophages from ST2(-/-) mice, we demonstrate that the IL-33 receptor, ST2, is integral to the action of IL-33 on macrophage foam cell formation. In conclusion, IL-33 has a protective role in atherosclerosis by reducing macrophage foam cell formation suggesting that IL-33 maybe a potential therapeutic agent against atherosclerosis. PMID:20543107

McLaren, James E; Michael, Daryn R; Salter, Rebecca C; Ashlin, Tim G; Calder, Claudia J; Miller, Ashley M; Liew, Foo Y; Ramji, Dipak P

2010-06-11

74

Epithelial cells in fetal intestine produce chemerin to recruit macrophages  

PubMed Central

Macrophages are first seen in the fetal intestine at 11–12 wk and rapidly increase in number during the 12- to 22-wk period of gestation. The development of macrophage populations in the fetal intestine precedes the appearance of lymphocytes and neutrophils and does not require the presence of dietary or microbial antigens. In this study, we investigated the role of chemerin, a recently discovered, relatively selective chemoattractant for macrophages, in the recruitment of macrophage precursors to the fetal intestine. Chemerin mRNA/protein expression was measured in jejunoileal tissue from 10- to 24-wk human fetuses, neonates operated for intestinal obstruction, and adults undergoing bariatric surgery. The expression of chemerin in intestinal epithelial cells (IECs) was confirmed by using cultured primary IECs and IEC-like cell lines in vitro. The regulatory mechanisms involved in chemerin expression were investigated by in silico and immunolocalization techniques. IECs in the fetal, but not mature, intestine express chemerin. Chemerin expression peaked in the fetal intestine at 20–24 wk and then decreased to original low levels by full term. During the 10- to 24-wk period, chemerin accounted for most of the macrophage chemotactic activity of cultured fetal IECs. The maturational changes in chemerin expression correlated with the expression of retinoic acid receptor-? in the intestine. Chemerin is an important mediator of epithelial-macrophage cross talk in the fetal/premature, but not in the mature, intestine. Understanding the regulation of the gut macrophage pool is an important step in development of novel strategies to boost mucosal immunity in premature infants and other patient populations at risk of microbial translocation.

Maheshwari, Akhil; Kurundkar, Ashish R.; Shaik, Sadiq S.; Kelly, David R.; Hartman, Yolanda; Zhang, Wei; Dimmitt, Reed; Saeed, Shehzad; Randolph, David A.; Aprahamian, Charles; Datta, Geeta; Ohls, Robin K.

2009-01-01

75

Peripheral blood mononuclear cell supernatants from asymptomatic dogs immunized and experimentally challenged with Leishmania chagasi can stimulate canine macrophages to reduce infection in vitro  

Microsoft Academic Search

Leishmania chagasi is the causative agent of visceral leishmaniasis in both humans and dogs in the New World. The dog is the main domestic reservoir and its infection displays different clinical presentations, from asymptomatic to severe disease. Macrophages play an important role in the control of Leishmania infection. Although it is not an area of intense study, some data suggest

Cleusa Alves Theodoro Rodrigues; Luís Fábio da Silva Batista; Márcia Cristina Aquino Teixeira; Andréa Mendes Pereira; Patrícia Oliveira Meira Santos; Geraldo Gileno de Sá Oliveira; Luiz Antônio Rodrigues de Freitas; Patrícia Sampaio Tavares Veras

2007-01-01

76

Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells.  

PubMed

Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer. PMID:24058644

Edin, Sofia; Wikberg, Maria L; Rutegård, Jörgen; Oldenborg, Per-Arne; Palmqvist, Richard

2013-09-18

77

Phenotypic Skewing of Macrophages In Vitro by Secreted Factors from Colorectal Cancer Cells  

PubMed Central

Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a “mixed” M1/M2 phenotype, which in turn could contribute to a “good inflammatory response”. This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.

Edin, Sofia; Wikberg, Maria L.; Rutegard, Jorgen; Oldenborg, Per-Arne; Palmqvist, Richard

2013-01-01

78

Migration inhibitory factor (MIF) released by macrophages upon recognition of immune complexes is critical to inflammation in Arthus reaction.  

PubMed

Deposition of immune complexes (IC) triggers Fc gamma R-dependent inflammation, leading to tissue damage in rheumatoid arthritis, systemic lupus erythematous, immune glomerulonephritis, and several immune vasculitides. Evidences support a role for macrophage migration inhibitory factor (MIF) in a number of inflammatory diseases, but the triggering of its secretion and its physiopathological role upon IC deposition remain elusive. Herein, we show that human macrophages secreted MIF after IC recognition, which in turn controlled the secretion of TNF. Macrophages from Mif-/- mice produced smaller amounts of TNF when stimulated with IgG-opsonized erythrocytes than wild-type (WT) cells. Using passive reverse Arthus reaction in the peritoneum and lungs as a model for IC-induced inflammation, we demonstrated that Mif-/- mice had a milder response, observed by reduced neutrophil recruitment, vascular leakage, and secretion of TNF, MIP-2, and keratinocyte-derived chemokine compared with WT controls. Adoptive transfer of alveolar macrophages from WT to Mif-/- mice rescued pulmonary neutrophil recruitment and TNF production upon passive reverse Arthus reaction. Our study indicates that Arthus inflammatory reaction is largely dependent on MIF and poses macrophages as a source of the MIF released upon IC recognition. These results give experimental support to the proposition that blockade of MIF might constitute an adjunctive, therapeutic approach to IC disease. PMID:19188484

Paiva, Claudia N; Arras, Rosa H; Magalhães, Elisabeth S; Alves, Letícia S; Lessa, Luiz Paulo; Silva, Maria Helena; Ejzemberg, Regina; Canetti, Cláudio; Bozza, Marcelo T

2009-02-02

79

Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor ? Linking Mannose Receptor Recognition to Regulation of Immune Responses  

PubMed Central

Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor ? (PPAR?), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPAR? expression through a macrophage mannose receptor-dependent pathway. When activated, PPAR? promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPAR? agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A2 activation, which is required for PPAR? ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-?B activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPAR? and preferentially uses the NF-?B–mediated pathway to induce IL-8 production. Finally, PPAR? knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPAR? activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.

Rajaram, Murugesan V. S.; Brooks, Michelle N.; Morris, Jessica D.; Torrelles, Jordi B.; Azad, Abul K.; Schlesinger, Larry S.

2010-01-01

80

Thrombospondin-1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells  

PubMed Central

Inhibition of tumor growth by thrombospondin-1 (TSP1) is generally attributed to its anti-angiogenic activity, but effects on tumor immunity should also be considered. We show that over-expression of TSP1 in melanoma cells increases macrophage recruitment into xenograft tumors grown in nude or beige/nude mice. In vitro, TSP1 acutely induces expression of plasminogen activator inhibitor-1 (PAI-1) by monocytic cells, suggesting that TSP1-induced macrophage recruitment is at least partially mediated by PAI-1. Tumor-associated macrophages can either promote or limit tumor progression. The percentage of M1 polarized macrophages expressing inducible nitric oxide synthase is increased in TSP1-expressing tumors. Furthermore, soluble TSP1 stimulates killing of breast carcinoma and melanoma cells by interferon-?-differentiated U937 cells in vitro via release of reactive oxygen species. TSP1 causes a significant increase in phorbol ester-mediated superoxide generation from differentiated monocytes by interaction with ?6?1 integrin through its N-terminal region. The N-terminal domain of thrombospondin-2 also stimulates monocyte superoxide production. Extracellular calcium is required for the TSP1-induced macrophage respiratory burst. Thus, TSP1 may play an important role in anti-tumor immunity by enhancing recruitment and activation of M1 tumor-associated macrophages, which provides an additional selective pressure for loss of TSP1 and thrombospondin-2 expression during tumor progression.

Martin-Manso, Gema; Galli, Susana; Ridnour, Lisa A.; Tsokos, Maria; Wink, David A.; Roberts, David D.

2008-01-01

81

Cytotoxicity of lambda-cyhalothrin on the macrophage cell line RAW 264.7  

Microsoft Academic Search

The wide use and wide-spectrum toxicity of synthetic pyrethroids (SPs) insecticides make them an emerging ecotoxicological concern. Some previous studies showed that SPs possessed cytotoxicity in some immune cells such as human lymphocytes and rat bone marrow. However, the cytotoxicity of SPs to macrophages, which are crucial to innate immunity, has not been explored. In the present report, we investigated

Quan Zhang; Cui Wang; Liwei Sun; Ling Li; Meirong Zhao

2010-01-01

82

Tumour necrosis factor and the lysosomal enzymes of macrophages or macrophage-like cell line  

Microsoft Academic Search

The relationship between tumour necrosis factor (TNF) and macrophages or macrophage-like cell line, especially the lysosomal enzymes was investigated. The serum lysosomal enzymes and LDH activities were increased in proportion to the TNF production even in different strains of mice. Lysosomal enzymes and TNF activity were released into the supernatant of the culture medium of macrophage-enriched peritoneal exudate cells (PEC)

Akiko Sakurai; Nobuko Satomi; Katsuyuki Haranaka

1985-01-01

83

5-Lipoxygenase contributes to PPAR? activation in macrophages in response to apoptotic cells.  

PubMed

Macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells is a contributing hallmark to immune suppression during the late phase of sepsis. Although the peroxisome proliferator-activated receptor ? (PPAR?) supports this macrophage phenotype switch, it remains elusive how apoptotic cells activate PPAR?. Assuming that a molecule causing PPAR? activation in macrophages originates in the cell membrane of apoptotic cells we analyzed lipid rafts from apoptotic, necrotic, and living human Jurkat T cells which showed the presence of 5-lipoxygenase (5-LO) in lipid rafts of apoptotic cells only. Incubating macrophages with lipid rafts of apoptotic, but not necrotic or living cells, induced PPAR responsive element (PPRE)-driven mRuby reporter gene expression in RAW 264.7 macrophages stably transduced with a 4xPPRE containing vector. Experiments with lipid rafts of apoptotic murine EL4 T cells revealed similar results. To verify the involvement of 5-LO in activating PPAR? in macrophages, Jurkat T cells were incubated with the 5-LO inhibitor MK-866 prior to induction of apoptosis, which failed to induce mRuby expression. Similar results were obtained with lipid rafts of apoptotic EL4 T cells preexposed to the 5-LO inhibitors zileuton and CJ-13610. Interestingly, Jurkat T cells overexpressing 5-LO failed to activate PPAR? in macrophages, while their 5-LO overexpressing apoptotic counterparts did. Our results suggest that during apoptosis 5-LO gets associated with lipid rafts and synthesizes ligands that in turn stimulate PPAR? in macrophages. PMID:24036216

von Knethen, Andreas; Sha, Lisa K; Kuchler, Laura; Heeg, Annika K; Fuhrmann, Dominik; Heide, Heinrich; Wittig, Ilka; Maier, Thorsten J; Steinhilber, Dieter; Brüne, Bernhard

2013-09-13

84

Immune cells in periapical granuloma: morphological and immunohistochemical characterization.  

PubMed

Samples of periapical granulomas obtained from 12 patients were examined using light and electron microscopes and monoclonal antibodies. Monocytes/macrophages, lymphocytes, and plasma cells were nearly always the most abundant cell populations. Ultrastructural analysis showed close contacts between macrophages and cells of the lymphoid lineage, with the lymphoid cells frequently demonstrating blastic features. Immunohistochemical staining with the anti-interleukin 2 receptor antibody showed that the concentration of labeled cells was quite low. The vast majority were lymphocytes, though some mast cells were also labeled. Mast cells were chiefly located in perivascular areas and interleukin 2 receptor-positive mast cells were frequently associated with lymphoid cells. mast cells could be part of a negative feedback mechanism in the immune response. By releasing histamine, they would block the immune response and by absorbing interleukin 2 they would remove it as an immune system stimulant. PMID:1895036

Piattelli, A; Artese, L; Rosini, S; Quaranta, M; Musiani, P

1991-01-01

85

The effect of altered gravity on immune cells (Ground studies: TRIPLE LUX-A BIOLAB experiment)  

Microsoft Academic Search

The experiment TRIPLE LUX A, whose performance on Biolab is foreseen for 2010, aims to increase the information about the functioning of immune cells during space flight. Thus, we investigate the impact of altered gravity -microgravity and hypergravity conditions -on the immune response of mammalian macrophages. Previous studies had already demonstrated that phagocytosis in macrophages, an essential step in the

Astrid Horn; Kathrin Huber; Ulrich Kuebler; Luca Briganti; Sven Baerwalde; Vanja Zander; Oliver Ullrich; Ruth Hemmersbach

2010-01-01

86

Mechanisms of Immunity in Typhus Infections II. Multiplication of Typhus Rickettsiae in Human Macrophage Cell Cultures in the Nonimmune System: Influence of Virulence of Rickettsial Strains and of Chloramphenicol  

PubMed Central

Monocytes from the peripheral blood of nonimmune human subjects transformed in cell culture into macrophages with increased phagocytic capacity for killed typhus rickettsiae. When such cells were exposed to living virulent Rickettsia mooseri (Wilmington strain) or R. prowazeki (Breinl strain), or to the attenuated E strain of R. prowazeki, in the presence of medium containing normal human serum, all three strains readily entered the macrophage, but the subsequent fate varied according to strain and its virulence. Thus, R. mooseri grew readily to attain very high intracellular populations which eventually destroyed the macrophage in 3 to 5 days and escaped to infect other cells. Virulent R. prowazeki also grew at about the same rate for the first 2 to 3 days but then often abruptly ceased to multiply. Circumstantial evidence suggests a toxic effect on host cells by smaller numbers of R. prowazeki organisms than with R. mooseri. The attenuated E strain of R. prowazeki failed to grow in most cells and eventually disappeared, but did grow to substantial numbers in the very rare cell in some cultures, suggesting the presence of a few cells which may not be typical macrophages. The growth of R. mooseri in the macrophage cytoplasm was inhibited by chloramphenicol in the culture medium. When the drug was removed after 3 days, growth began after a lag period and assumed a normal rate. Images

Gambrill, Margaret R.; Wisseman, C. L.

1973-01-01

87

Effects of T-2 Toxin on Cytokine Production by Mice Peritoneal Macrophages and Lymph Node T-Cells  

Microsoft Academic Search

Background: T-2 toxin is a mycotoxin of type A trichothecenes produced by several fungal genera such as Fusarium species. Mycotoxins can affect both cell mediated and humoral immune compartments. Objective: The purpose of this study was to investi- gate the effect of T-2 toxin on cytokine production by mouse peritoneal macrophages and lymph node T cells. Methods: Mouse peritoneal macrophages

Kazem Ahmadi; Majid Riazipour

88

Uropathogenic E. coli induce different immune response in testicular and peritoneal macrophages: implications for testicular immune privilege.  

PubMed

Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM) respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages (PM) infected with uropathogenic E. coli (UPEC) revealed major differences in regulated genes. However, a multitude of genes implicated in calcium signaling pathways was a common feature which indicated a role of calcium-dependent nuclear factor of activated T cells (NFAT) signaling. UPEC-dependent NFAT activation was confirmed in both cultured TM and in TM in an in vivo UPEC infectious rat orchitis model. Elevated expression of NFATC2-regulated anti-inflammatory cytokines was found in TM (IL-4, IL-13) and PM (IL-3, IL-4, IL-13). NFATC2 is activated by rapid influx of calcium, an activity delineated to the pore forming toxin alpha-hemolysin by bacterial mutant analysis. Alpha-hemolysin suppressed IL-6 and TNF-? cytokine release from PM and caused differential activation of MAP kinase and AP-1 signaling pathways in TM and PM leading to reciprocal expression of key pro-inflammatory cytokines in PM (IL-1?, IL-1?, IL-6 downregulated) and TM (IL-1?, IL-6 upregulated). In addition, unlike PM, LPS-treated TM were refractory to NF?B activation shown by the absence of degradation of I?B? and lack of pro-inflammatory cytokine secretion (IL-6, TNF-?). Taken together, these results suggest a mechanism to the conundrum by which TM initiate immune responses to bacteria, while maintaining testicular immune privilege with its ability to tolerate neo-autoantigens expressed on developing spermatogenic cells. PMID:22164293

Bhushan, Sudhanshu; Hossain, Hamid; Lu, Yongning; Geisler, Andreas; Tchatalbachev, Svetlin; Mikulski, Zbigniew; Schuler, Gerhard; Klug, Jörg; Pilatz, Adrian; Wagenlehner, Florian; Chakraborty, Trinad; Meinhardt, Andreas

2011-12-02

89

Further characterization of macrophage adsorption of suppressor cell activity from tumor-allosensitized spleen  

SciTech Connect

Suppressor cell activity from P815-allosensitized C57BL/6 spleen can be decreased by incubating the tumor-allosensitized spleen cells on monolayers of thioglycollate-stimulated BDF1 peritoneal macrophages for 2 or 4 hr. The adsorption response appears to be specific for macrophages, because adsorption of suppressor cell activity does not occur following incubation of P815-allosensitized spleen cells on confluent monolayers of mouse spleen cells or mouse embryonic fibroblasts. Pretreatment of macrophage monolayers with X irradiation (2,000 rads) or anti-Thy 1.2 serum (and complement) does not affect their ability to bind suppressor cell activity. Adsorption of suppressor cell activity from P815-allosensitized spleen can also be carried out by proteose peptone-stimulated or Corynebacterium parvum-stimulated macrophages. Blockage of macrophage Fc receptors decreases the ability of thioglycollate-stimulated macrophages to adsorb suppressor cell activity. Monolayers of P815 or P388 cells, two cell types positive for Fc receptors, are unable to adsorb suppressor cell activity from the tumor-allosensitized spleen. The significance of our findings is discussed in terms of the relationship between macrophages and suppressor cells in the immune response to normal or tumor allografts.

Zografos-Miller, L.E.; Argyris, B.F.

1983-06-01

90

Effect of HeNe laser irradiation on the phagocytosis of macrophages in the immune organs of mice  

NASA Astrophysics Data System (ADS)

In order to study the effect of HeNe laser on macrophages phagocytosis, the are over liver and spleen of the mice was irradiated with NeHe laser at the dosage of 63.7J/cm2 for 3,5,7, and 10 days respectively, 5 min each day, then observing the phagocytosis of macrophages of the immune organs after trypan blue injecting live mice, and made quantitative analysis of macrophages phagocytosis by image analysis system. The results showed that the four indexes: number of trypan blue granule (GN), area of granule (GA), ratio of granule area to cell area (GA/CA) and granule integral optical density (IOD) at irradiated groups were higher than that of control group (P<0.01). Comparison between different irradiated groups were higher than that of control group (P<0.01). The study indicated that HeNe laser with appropriate dosage can activate macrophages of the immune organs, and enhance their organic immunity.

Ren, Mingji; Shi, Yonghong; Wang, Jianwei; Yuan, Weizhong

2000-10-01

91

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

92

Immune stimulatory effects of Loranthi ramulus on macrophages through the increase of NO and TNF-alpha.  

PubMed

The activation of macrophages by microorganisms plays an important role in host defense and immunopathology. Loranthi ramulus (LR) is commonly used as a traditional drug and health food in Korea. Here, we investigated the regulatory effects of LR on macrophage-mediated immune responses. Treatment of macrophages with LR resulted in the enhanced cell-surface expression of CD80, CD86 and major histocompatibility complex (MHC) class II, as well as the enhanced production of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha, and also iNOS and TNF-alpha mRNA expression. These alterations of LR-treated cells were associated with the activation of NF-kappaB and mitogen-activated protein kinases (MAPKs). LR increased the phosphorylation of MAPKs (JNK, ERK1/2, p38 MAPK) and the activation of NF-kappaB in Raw 264.7 cells. These results suggest that LR has increased NO and TNF-alpha production through phosphorylation of all three MAPKs following IkappaBalpha degradation and NF-kappaB activation. In conclusion, our results demonstrate that LR can effectively promote the activation of macrophages, suggesting that LR may possess the potential to regulate immune responses. PMID:19555217

Shin, Hye Young; Chang, In Ae; Zhang, Wen Ji; Kim, Youn Chul; Yuun, Yong Gab; Park, Hyun

2009-01-01

93

Human macrophage hybrid forming spontaneous giant cells  

Microsoft Academic Search

Summary  Thymidine kinase-deficient clones of the human monocyte\\/ macrophage cell line U-937 were established and used for fusion experiments\\u000a with separated normal human blood monocytes. A hybrid (H 29) was generated during HAT-selection procedure, about 50% of which\\u000a formed spontaneous giant cells, as shown by morphological, immunocytochemical, and chromosomal analyses. It is concluded that\\u000a giant cells originate from monocytes and display

Mohammad R. Parwaresch; Hans Kreipe; Heinz J. Radzun

1986-01-01

94

The interplay between Salmonella typhimurium and its macrophage host--what can it teach us about innate immunity?  

PubMed

Salmonella enterica sv. Typhimurium (S. typhimurium) is a genetically tractable, facultative intracellular pathogen, whose capacity to cause systemic disease in mice depends upon its ability to survive and replicate within macrophages. The identification of Salmonella mutants that lack this activity, has provided a tool with which to dissect the mechanisms used by Salmonella to establish a permissive niche, and identify host activities which it must overcome in order to achieve this. Salmonella actively maintains itself within an intracellular vacuole, thereby shielding itself from an antibacterial activity of host macrophage cytosol. Salmonella controls the maturation of its vacuole, segregating itself from the macrophage degradative pathway. Like several other pathogens, Salmonella reduces the effectiveness of bacteriocidal and bacteriostatic free radicals generated by macrophages, by synthesising enzymes and products that counteract them. Recent evidence indicates that Salmonella also avoids free radical-dependent macrophage antimicrobial mechanisms by more novel means. Here, we review recent studies of the interplay between pathogen and host, with particular emphasis on those areas that suggest new facets to the cell biology of macrophages, and their innate immune functions. PMID:12527226

Linehan, Sheena A; Holden, David W

2003-01-22

95

Infection of Primary Bovine Macrophages with Mycobacterium avium Subspecies paratuberculosis Suppresses Host Cell Apoptosis  

PubMed Central

Mycobacterium avium subspecies paratuberculosis (MAP) is able to survive intracellularly in macrophages by preventing normal phagosome maturation processes utilized to destroy bacteria. Infected macrophages often undergo apoptotic cell death to efficiently present bacterial antigens to the host adaptive immune system in a process known as efferocytosis. Recent studies with Mycobacterium tuberculosis (MTB) showed that macrophages infected with MTB are less likely to undergo apoptosis than control, uninfected cells. It is proposed that regulation of macrophage apoptosis is an important immune evasion tactic for MTB. Based on the similarity of MAP and MTB, we hypothesized that MAP-infected macrophages would be resistant to apoptosis compared to uninfected cells within the same culture and to cells from uninfected cultures. Our results demonstrate that, indeed, populations of MAP-infected macrophages contain fewer apoptotic cells than similar populations of control cells, and that MAP infection reduces the sensitivity of infected macrophages to induction of apoptosis by H2O2. We further demonstrate that MAP-infected cells contain reduced caspase activity for caspases 3/7, 8, and 9. Reduced caspase activity in MAP-infected macrophages is also maintained after H2O2 induction. This reduction in caspase activity is accompanied by a pronounced reduction in transcription of caspase genes encoding caspases 3, 7, and 8, but not for caspase 9, when compared to control, uninfected cells. Furthermore, MAP infection drastically effects the expression of several host cell proteins important for regulation of apoptosis. Studies using mutant MAP strains demonstrate the importance of bacterial specific factors in the control of host macrophage apoptosis. Together these data demonstrate that MAP specific factors may prevent caspase activity and caspase gene transcription as well as apoptosis signaling protein expression, resulting in decreased spontaneous host cell apoptosis and decreased sensitivity to apoptosis inducing agents.

Kabara, Edward; Coussens, Paul M.

2012-01-01

96

Resident macrophages influence stem cell activity in the mammary gland  

Microsoft Academic Search

INTRODUCTION: Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis. Although it is well established that macrophages influence normal mammopoiesis, the mammary cell types that these accessory cells influence have not been determined. Here we have explored a role for macrophages in regulating mammary stem cell

David E Gyorki; Marie-Liesse Asselin-Labat; Nico van Rooijen; Geoffrey J Lindeman; Jane E Visvader

2009-01-01

97

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

98

MFG-E8 released by apoptotic endothelial cells triggers anti-inflammatory macrophage reprogramming.  

PubMed

Apoptotic endothelial cells are an important component of the "response to injury" process. Several atherosclerosis risk factors such as hyperglycemia and oxidized low-density lipoproteins, and immune injuries, such as antibodies and complement, induce endothelial cell apoptosis. While endothelial cell apoptosis is known to affect neighboring vascular wall cell biology, its consequences on macrophage reprogramming are ill defined. In this study, we report that apoptosis of human and mouse endothelial cells triggers the release of milk fat globule-epidermal growth factor 8 (MFG-E8) and reprograms macrophages into an anti-inflammatory cells. We demonstrated that MFG-E8 is released by apoptotic endothelial cells in a caspase-3-dependent manner. When macrophages were exposed to conditioned media from serum-starved apoptotic endothelial cells, they adopt a high anti-inflammatory, low pro-inflammatory cytokine/chemokine secreting phenotype that is lost if MFG-E8 is absent from the media. Macrophage treatment with recombinant MFG-E8 recapitulates the effect of conditioned media. Finally, we showed that MFG-E8-mediated reprogramming of macrophages occurs through increased phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Taken together, our study suggests a key role of MFG-E8 release from apoptotic endothelial cells in macrophage reprogramming and demonstrates the importance of the apoptotic microenvironment in anti-inflammatory macrophage responses. PMID:22558449

Brissette, Marie-Joëlle; Lepage, Stéphanie; Lamonde, Anne-Sophie; Sirois, Isabelle; Groleau, Jessika; Laurin, Louis-Philippe; Cailhier, Jean-François

2012-04-30

99

Intestinal immune cells in Strongyloides stercoralis infection.  

PubMed Central

BACKGROUND: Strongyloides stercoralis can cause a wide spectrum of disease in man, ranging from a chronic asymptomatic infection to a hyperinfective, often fatal syndrome. In rodents, spontaneous expulsion of Strongyloides spp occurs after experimental infection. Mast cells, goblet cells, and eosinophils have been identified as possible effectors of this expulsion. AIMS: To investigate intestinal histopathology and mucosal immunity in immunocompetent patients with chronic S stercoralis infection. METHODS: Jejunal biopsies were performed in 19 immunocompetent patients with a positive stool examination for S stercoralis and few or no symptoms, and in seven healthy controls. Specimens were processed for histopathological analysis and stained by the immunoperoxidase technique, using the following monoclonal antibodies: CD2, CD3, CD4, CD8, anti-T cell receptor (TcR) gamma/delta, RFD1 and RFD7 (two different macrophage markers), Ki67+ (proliferating) cells, antihuman leucocyte antigen (HLA)-DR, and anticollagen IV. In addition, CD25+ cells, mast cells, IgE expressing cells, calprotectin containing cells, and neutrophil elastase positive cells were stained by the alkaline phosphatase method. RESULTS: Jejunal morphology and the numbers of different T cell subsets, mast cells, IgE expressing cells, eosinophils, and goblet cells were unaffected by S stercoralis infection. Conversely, the numbers of mature macrophages and dividing enterocytes in the crypts were reduced significantly. Crypt enterocytes did not express HLA-DR in both groups. The expression of HLA-DR by villus enterocytes was also comparable in patients and controls. There were no activated (CD25+) cells in the mucosa of either patients or controls. CONCLUSIONS: Compared with seven healthy uninfected volunteers, a group of 19 Brazilians with clinically mild strongyloides infection showed no abnormality of mucosal structure and no increase in non-specific inflammatory cells. Likewise, there was no increase in mucosal T cells or macrophages. Images

Trajman, A; MacDonald, T T; Elia, C C

1997-01-01

100

CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis  

PubMed Central

Cell migration and phagocytosis are both important for controlling Mycobacterium tuberculosis infection and are critically dependent on the reorganization of the cytoskeleton. Since CD44 is an adhesion molecule involved in inflammatory responses and is connected to the actin cytoskeleton, we investigated the role of CD44 in both these processes. Macrophage (M?) recruitment into M. tuberculosis–infected lungs and delayed-type hypersensitivity sites was impaired in CD44-deficient (CD44–/–) mice. In addition, the number of T lymphocytes and the concentration of the protective key cytokine IFN-? were reduced in the lungs of infected CD44–/– mice. The production of IFN-? by splenocytes of CD44–/– mice was profoundly increased upon antigen-specific stimulation. Flow cytometry analysis revealed that soluble CD44 can directly bind to virulent M. tuberculosis. Mycobacteria also interacted with M?-associated CD44, as reflected by reduced binding and internalization of bacilli by CD44–/– M?s. This suggests that CD44 is a receptor on M?s for binding of M. tuberculosis. CD44–/– mice displayed a decreased survival and an enhanced mycobacterial outgrowth in lungs and liver during pulmonary tuberculosis. In summary, we have identified CD44 as a new M? binding site for M. tuberculosis that mediates mycobacterial phagocytosis, M? recruitment, and protective immunity against pulmonary tuberculosis.

Leemans, Jaklien C.; Florquin, Sandrine; Heikens, Mirjam; Pals, Steven T.; Neut, Ronald van der; van der Poll, Tom

2003-01-01

101

Uropathogenic E. coli Induce Different Immune Response in Testicular and Peritoneal Macrophages: Implications for Testicular Immune Privilege  

Microsoft Academic Search

Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM) respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages

Sudhanshu Bhushan; Hamid Hossain; Yongning Lu; Andreas Geisler; Svetlin Tchatalbachev; Zbigniew Mikulski; Gerhard Schuler; Jörg Klug; Adrian Pilatz; Florian Wagenlehner; Trinad Chakraborty; Andreas Meinhardt

2011-01-01

102

Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses.  

PubMed

Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence seems to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8(+) T lymphocytes. Together, our findings show how targeting TAMs can effectively overcome therapeutic resistance mediated by TICs. PMID:23221383

Mitchem, Jonathan B; Brennan, Donal J; Knolhoff, Brett L; Belt, Brian A; Zhu, Yu; Sanford, Dominic E; Belaygorod, Larisa; Carpenter, Danielle; Collins, Lynne; Piwnica-Worms, David; Hewitt, Stephen; Udupi, Girish Mallya; Gallagher, William M; Wegner, Craig; West, Brian L; Wang-Gillam, Andrea; Goedegebuure, Peter; Linehan, David C; DeNardo, David G

2012-12-05

103

Delayed clearance of filarial infection and enhanced Th1 immunity due to modulation of macrophage APC functions in xid mice.  

PubMed

Bruton's tyrosine kinase (Btk) mutant CBA/N mice show delayed clearance of injected microfilaria (mf) compared with wild-type CBA/J mice. Anti-mf T cells from CBA/N mice make relatively more IFN-gamma than those from CBA/J mice. The anti-mf T cell proliferative responses are also greater in CBA/N mice. This CBA/N immune phenotype is not restricted to filarial Ags, because immunization with pure proteins also yields T cell responses of greater proliferative magnitude skewed away from Th2 cytokines in CBA/N compared with CBA/J mice. The increased magnitude of CBA/N T cell proliferative responses is reflected in increases in both precursor frequencies and clonal burst sizes of responding Ag-specific T cells, and is independent of the source of re-stimulating APCs. Transfer of CBA/J peritoneal resident cells (PRCs) into CBA/N mice before pure protein immunization leads to a wild-type immune phenotype in the recipient CBA/N mice, with a reduction in the proliferative response and a relative decrease in the IFN-gamma produced. When wild-type PRC subpopulations are similarly transferred, the wild-type immune phenotype is transferred by macrophages rather than by B cells. Transfer of wild-type PRCs into CBA/N mice before injection of mf also causes similar changes in the anti-mf T cell responses and enhances the clearance of mf. Thus, Btk is involved in critical macrophage APC functions regulating priming of T cells, and can modulate these responses in pathophysiologically relevant fashion in vivo. PMID:10395682

Mukhopadhyay, S; Sahoo, P K; George, A; Bal, V; Rath, S; Ravindran, B

1999-07-15

104

Progressive growth of a murine T cell lymphoma alters population kinetics and cell viability of macrophages in a tumor-bearing host.  

PubMed

Tumor progression induces infiltration of immune cell populations at the site of tumor growth. Infiltrated leukocyte population including monocyte and macrophages interacts with tumor cells and tumor microenvironment and results in the suppression of macrophage functions. Impaired functions of macrophages result in the suppression/inhibition of cell-mediated immunity leading to inefficient antitumor immune responses. Impaired macrophage population invariably helps in immune selection of tumor leading to uninterrupted growth and progression in the host. Murine T cell lymphoma designated as Dalton's lymphoma is highly immunosuppressive and invasive tumor of T cell origin, which completely paralyzes the host's immune system resulting in a very short life span of the host. Progressive growth of Dalton's lymphoma (DL) cells has been known to inhibit the release of inflammatory cytokines and effector mediator molecules. In this study, we demonstrate that intraperitoneal transplant of DL cells in normal healthy host induces a rapid increase in macrophage cell population during early stage of tumor progression and progressive decrease in tumor-associated macrophage population and reduced survival of macrophages in advance stage of tumor burden. PMID:23247866

Gautam, Pramod K; Maurya, Babu N; Kumar, Sanjay; Deepak, Praveen; Kumar, Sanjay; Tomar, Munendra S; Acharya, Arbind

2012-12-18

105

A common path to innate immunity to HIV-1 induced by Toll-like receptor ligands in primary human macrophages.  

PubMed

Toll-like receptors (TLR) represent the best characterized receptor family transducing innate immune responses, the first line of defense against microbial invaders. This study was designed to investigate whether responses through TLR inhibit HIV-1 replication in its primary target cells. Primary human macrophages and lymphocytes from several different donors and HIV-1 infection in tissue culture were used exclusively in this work. We report that ligands of three different TLR: LPS, R848, and double stranded RNA, induce a common antiviral response in macrophages as assayed by measurement of HIV-1 p24 protein, gag DNA, and entry into cells. HIV-1 infection is arrested after efficient entry but prior to reverse transcription. TLR-ligand activated cells secrete antiviral factors that induce a similar restriction. HIV-1 infection of lymphocytes is not affected by exposure to TLR ligands or to antiviral factors secreted by activated macrophages. TBK1, but neither NF-?B nor JAK-STAT activity, is required in macrophages to mount this antiviral response; the combination of p38 MAPK and JNK are partially required for induction of antiviral activity. Based on transcriptional induction and inhibition, the TLR-linked antiviral activity is different from APOBEC3 A or G, interferon-?, NAMPT, or p21(Cip1). The cell-type specificity, site of action, and requirement for signaling intermediates suggest that the TLR-linked antiviral activity is novel. PMID:21904615

Wang, Xingyu; Chao, Wei; Saini, Manisha; Potash, Mary Jane

2011-08-31

106

A Common Path to Innate Immunity to HIV-1 Induced by Toll-Like Receptor Ligands in Primary Human Macrophages  

PubMed Central

Toll-like receptors (TLR) represent the best characterized receptor family transducing innate immune responses, the first line of defense against microbial invaders. This study was designed to investigate whether responses through TLR inhibit HIV-1 replication in its primary target cells. Primary human macrophages and lymphocytes from several different donors and HIV-1 infection in tissue culture were used exclusively in this work. We report that ligands of three different TLR: LPS, R848, and double stranded RNA, induce a common antiviral response in macrophages as assayed by measurement of HIV-1 p24 protein, gag DNA, and entry into cells. HIV-1 infection is arrested after efficient entry but prior to reverse transcription. TLR-ligand activated cells secrete antiviral factors that induce a similar restriction. HIV-1 infection of lymphocytes is not affected by exposure to TLR ligands or to antiviral factors secreted by activated macrophages. TBK1, but neither NF-?B nor JAK-STAT activity, is required in macrophages to mount this antiviral response; the combination of p38 MAPK and JNK are partially required for induction of antiviral activity. Based on transcriptional induction and inhibition, the TLR-linked antiviral activity is different from APOBEC3 A or G, interferon-?, NAMPT, or p21Cip1. The cell-type specificity, site of action, and requirement for signaling intermediates suggest that the TLR-linked antiviral activity is novel.

Wang, Xingyu; Chao, Wei; Saini, Manisha; Potash, Mary Jane

2011-01-01

107

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

PubMed

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; Weiss, Günter

2013-04-29

108

Exosomes Derived from M. Bovis BCG Infected Macrophages Activate Antigen-Specific CD4+ and CD8+ T Cells In Vitro and In Vivo  

Microsoft Academic Search

Activation of both CD4+ and CD8+ T cells is required for an effective immune response to an M. tuberculosis infection. However, infected macrophages are poor antigen presenting cells and may be spatially separated from recruited T cells, thus limiting antigen presentation within a granuloma. Our previous studies showed that infected macrophages release from cells small membrane-bound vesicles called exosomes which

Pramod K. Giri; Jeffrey S. Schorey; William Bishai

2008-01-01

109

Frustrated Phagocytosis on Micro-Patterned Immune Complexes to Characterize Lysosome Movements in Live Macrophages  

PubMed Central

Lysosome mobilization is a key cellular process in phagocytes for bactericidal activities and trans-matrix migration. The molecular mechanisms that regulate lysosome mobilization are still poorly known. Lysosomes are hard to track as they move toward phagosomes throughout the cell volume. In order to anticipate cell regions where lysosomes are recruited to, human and RAW264.7 macrophages were seeded on surfaces that were micro-patterned with immune complexes (ICs) as 4??m-side squares. Distances between IC patterns were adapted to optimize cell spreading in order to constrain lysosome movements mostly in two dimensions. Fc? receptors triggered local frustrated phagocytosis, frustrated phagosomes appeared as rings of F-actin dots around the IC patterns as early as 5?min after cells made contact with the substratum. Frustrated phagosomes recruited actin-associated proteins (vinculin, paxillin, and gelsolin). The fusion of lysosomes with frustrated phagosomes was shown by the release of beta-hexosaminidase and the recruitment of Lamp1 to frustrated phagosomes. Lysosomes of RAW264.7 macrophages were labeled with cathepsin-D-mCherry to visualize their movements toward frustrated phagosomes. Lysosomes saltatory movements were markedly slowed down compared to cells layered on non-opsonized patterns. In addition, the linearity of the trajectories and the frequency and duration of contacts of lysosomes with frustrated phagosomes were measured. Our experimental set-up is the first step toward deciphering molecular mechanisms which are involved in lysosome movements in the cytoplasm (speed, directionality, and interaction with phagosomes), and opens the door to approaches such as RNA interference, pharmacological inhibition, or mutant expression.

Labrousse, Arnaud M.; Meunier, Etienne; Record, Julien; Labernadie, Anna; Beduer, Amelie; Vieu, Christophe; Ben Safta, Thouraya; Maridonneau-Parini, Isabelle

2011-01-01

110

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.

Gray, Elizabeth E.; Cyster, Jason G.

2013-01-01

111

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. ...

112

Regulation of cancer stem cell activities by tumor-associated macrophages  

PubMed Central

Recent studies revealed that tumor-associated macrophages play a decisive role in the regulation of tumor progression by manipulating tumor oncogenesis, angiogenesis and immune functions within tumor microenvironments. However, the role of cancer stem cells in the tumorigenic activities of tumor-associated macrophages during the course of transformation and treatment remains largely unknown. Recent studies have clarified the functional aspects of tumor-associated macrophages in the regulation of the tumorigenic activities and anticancer drug responsiveness of cancer stem cells through complex networks formed by distinct sets of cytokines, chemokines and growth factors. In this article we discuss recent advances and future perspectives regarding the molecular interplay between cancer stem cells and tumor-associated macrophages and provide future perspective about the therapeutic implication against treatment-resistant variants of cancer.

Jinushi, Masahisa; Baghdadi, Muhammad; Chiba, Shigeki; Yoshiyama, Hironori

2012-01-01

113

New Lives Given by Cell Death: Macrophage Differentiation Following Their Encounter with Apoptotic Leukocytes during the Resolution of Inflammation  

PubMed Central

Monocytes that migrate into tissues during inflammatory episodes and differentiate to macrophages were previously classified as classically (M1) or alternatively (M2) activated macrophages, based on their exposure to different fate-determining mediators. These macrophage subsets display distinct molecular markers and differential functions. At the same time, studies from recent years found that the encounter of apoptotic leukocytes with macrophages leads to the clearance of this cellular “debris” by the macrophages, while concomitantly reprogramming/immune-silencing the macrophages. While some of the features of M2 differentiation, such as arginase-1 (murine) and 15-lipoxygenases (human and murine) expression, were also displayed by macrophages following the engulfment of apoptotic cells, it was not clear whether apoptotic cells can be regarded as an M2-like differentiating signal. In this manuscript we review the recent information regarding the impact of apoptotic cells on macrophage phenotype changes in molecular terms. We will focus on recent evidence for the in vivo existence of distinct pro-resolving macrophages and the role of apoptotic cells, specialized lipid mediators, and glucocorticoids in their generation. Consequently, we will suggest that these pro-resolving CD11blow macrophages have metamorphed from M2-like macrophages, and modulated their protein profile to accommodate the changes in their function.

Ariel, Amiram; Serhan, Charles N.

2012-01-01

114

Differential Trafficking of Oxidized LDL and Oxidized LDL Immune Complexes in Macrophages: Impact on Oxidative Stress  

PubMed Central

Background Oxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). It has been shown that oxLDL-IC are considerably more efficient than oxLDL in induction of foam cell formation, inflammatory cytokines secretion, and cell survival promotion. Whereas oxLDL is taken up by several scavenger receptors, oxLDL-IC are predominantly internalized through the FC? receptor I (FC? RI). This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress. Methodology/Findings Fluorescently labeled lipid and protein moieties of oxLDL co-localized within endosomal and lysosomal compartments in U937 human monocytic cells. In contrast, the lipid moiety of oxLDL-IC was detected in the endosomal compartment, whereas its apolipoprotein moiety advanced to the lysosomal compartment. Cells treated with oxLDL-IC prior to oxLDL demonstrated co-localization of internalized lipid moieties from both oxLDL and oxLDL-IC in the endosomal compartment. This sequential treatment likely inhibited oxLDL lipid moieties from trafficking to the lysosomal compartment. In RAW 264.7 macrophages, oxLDL-IC but not oxLDL induced GFP-tagged heat shock protein 70 (HSP70) and HSP70B', which co-localized with the lipid moiety of oxLDL-IC in the endosomal compartment. This suggests that HSP70 family members might prevent the degradation of the internalized lipid moiety of oxLDL-IC by delaying its advancement to the lysosome. The data also showed that mitochondrial membrane potential was decreased and generation of reactive oxygen and nitrogen species was increased in U937 cell treated with oxLDL compared to oxLDL-IC. Conclusions/Significance Findings suggest that lipid and apolipoprotein moieties of oxLDL-IC traffic to separate cellular compartments, and that HSP70/70B' might sequester the lipid moiety of oxLDL-IC in the endosomal compartment. This mechanism could ultimately influence macrophage function and survival. Furthermore, oxLDL-IC might regulate the intracellular trafficking of free oxLDL possibly through the induction of HSP70/70B'.

Al Gadban, Mohammed M.; Smith, Kent J.; Soodavar, Farzan; Piansay, Christabelle; Chassereau, Charlyne; Twal, Waleed O.; Klein, Richard L.; Virella, Gabriel; Lopes-Virella, Maria F.; Hammad, Samar M.

2010-01-01

115

Regulatory effects of Codonopsis lanceolata on macrophage-mediated immune responses.  

PubMed

Codonopsis lanceolata L. has long been used as a folk medicine in Korea, Japan and China for the treatment of lung inflammatory diseases. In this study, therefore, we aimed to demonstrate its ethnopharmacological activity by examining macrophage-function regulating effects. The total methanol extracts of fresh leaves (l-TME) or roots (r-TME) of Codonopsis lanceolata L. significantly suppressed the production of pro-inflammatory mediators (nitric oxide [NO] and tumor necrosis factor [TNF-alpha]) without altering mRNA levels. The expression of interleukin (IL)-3 and IL-6, however, was strongly diminished. According to the analysis of signaling enzyme activation by immunoblotting, phospho-IkappaB levels, a representative pro-inflammatory gene activation pathway, were not affected by the TMEs. By contrast, the Raf-ERK signaling pathway, which was involved in regulation of post-translational modification of pro-inflammatory gene products, was strongly blocked after 6-h of exposure. Moreover, l-TME down-regulated LPS-mediated phagocytic uptake and CD29-mediated cell-cell adhesion, while r-TME strongly up-regulated these two cellular events as well as fibronectin-cell adhesion. The surface levels of the costimulatory molecules (CD80 and CD86) of RAW264.7 cells were also enhanced by these extracts. l-TME also diminished functional activation (assessed by NO production) and the surface level of dectin-1, but not toll-like receptor (TLR)-2. Taken together, these data suggest that Codonopsis lanceolata may have the ability to modulate macrophage-mediated immune responses, thus contributing to its anti-inflammatory activity. PMID:17418512

Lee, Yong Gyu; Kim, Joo Young; Lee, Ji Yeon; Byeon, Se Eun; Hong, Eock Kee; Lee, Jaehwi; Rhee, Man Hee; Park, Hwa Jin; Cho, Jae Youl

2007-03-06

116

Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages.  

PubMed

Basal-like breast cancer (BBC) is an aggressive subtype of breast cancer that has no biologically targeted therapy. The interactions of BBCs with stromal cells are important determinants of tumor biology, with inflammatory cells playing well-recognized roles in cancer progression. Despite the fact that macrophage-BBC communication is bidirectional, important questions remain about how BBCs affect adjacent immune cells. This study investigated monocyte-to-macrophage differentiation and polarization and gene expression in response to coculture with basal-like versus luminal breast cancer cells. Changes induced by coculture were compared with changes observed under classical differentiation and polarization conditions. Monocytes (THP-1 cells) exposed to BBC cells in coculture had altered gene expression with upregulation of both M1 and M2 macrophage markers. Two sets of M1 and M2 markers were selected from the PCR profiles and used for dual immunofluorescent staining of BBC versus luminal cocultured THP-1s, and cancer-adjacent, benign tissue sections from patients diagnosed with BBCs or luminal breast cancer, confirming the differential expression patterns. Relative to luminal breast cancers, BBCs also increased differentiation of monocytes to macrophages and stimulated macrophage migration. Consistent with these changes in cellular phenotype, a distinct pattern of cytokine secretion was evident in macrophage-BBC cocultures, including upregulation of NAP-2, osteoprotegerin, MIG, MCP-1, MCP-3, and interleukin (IL)-1?. Application of IL-1 receptor antagonist (IL-1RA) to cocultures attenuated BBC-induced macrophage migration. These data contribute to an understanding of the BBC-mediated activation of the stromal immune response, implicating specific cytokines that are differentially expressed in basal-like microenvironments and suggesting plausible targets for modulating immune responses to BBCs. PMID:22532586

Stewart, Delisha A; Yang, Yinmeng; Makowski, Liza; Troester, Melissa A

2012-04-24

117

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

118

Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer.  

PubMed

Background:The host immune reaction is represented by immune/inflammatory cell infiltrates. Here we systematically analysed tumour-infiltrating immune/inflammatory cells in pancreatic ductal carcinoma (PDC) and evaluated their clinicopathological impact.Methods:Using immunohistochemistry, we examined tumour-infiltrating CD68(+) pan-macrophages, HLA-DR(+)CD68(+) M1 macrophages (M1), CD163(+) or CD204(+) M2 macrophages (M2), CD66b(+) neutrophils (Neu), CD4(+) T cells (CD4(+)T), CD8(+) T cells (CD8(+)T), and FOXP3(+)CD4(+) regulatory T cells (Treg) in 212 cases of PDC, and conducted correlation and survival analyses using the Kaplan-Meier method and Cox proportional hazards model.Results:Higher levels of tumour-infiltrating pan-macrophages, M2, Neu, or the ratio of Tregs to CD4(+)T (%Treg) were significantly associated with shorter survival, whereas higher levels of tumour-infiltrating CD4(+)T, CD8(+)T, or the ratio of M1 to pan-macrophages (%M1) were significantly associated with longer survival. Survival analysis of pairs of these variables revealed that some of the resulting patient groups had exclusively longer survival. We then connected the apparently related factors, and two significant variables emerged: tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and tumour-infiltrating %M1(high)/M2(low). Multivariate survival analysis revealed that these variables were significantly correlated with longer survival and had a higher hazard ratio.Conclusion:Tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and %M1(high)/M2(low) are independent prognosticators useful for evaluating the immune microenvironment of PDC. PMID:23385730

Ino, Y; Yamazaki-Itoh, R; Shimada, K; Iwasaki, M; Kosuge, T; Kanai, Y; Hiraoka, N

2013-02-05

119

Glioma cancer stem cells induce immunosuppressive macrophages/microglia.  

PubMed

Macrophages (M?s)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of M?s/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated M? inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-?1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of M?/microglia phagocytosis, induction of M?/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-?1, and MIC-1, cytokines known to recruit and polarize the M?s/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the M?/microglia to an M2 phenotype, inhibited M?/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-?1 by the M?s/microglia, and enhanced the capacity of M?s/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive M?s/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3. PMID:20667896

Wu, Adam; Wei, Jun; Kong, Ling-Yuan; Wang, Yongtao; Priebe, Waldemar; Qiao, Wei; Sawaya, Raymond; Heimberger, Amy B

2010-07-28

120

Glioma cancer stem cells induce immunosuppressive macrophages/microglia  

PubMed Central

Macrophages (M?s)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of M?s/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated M? inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-?1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of M?/microglia phagocytosis, induction of M?/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-?1, and MIC-1, cytokines known to recruit and polarize the M?s/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the M?/microglia to an M2 phenotype, inhibited M?/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-?1 by the M?s/microglia, and enhanced the capacity of M?s/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive M?s/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.

Wu, Adam; Wei, Jun; Kong, Ling-Yuan; Wang, Yongtao; Priebe, Waldemar; Qiao, Wei; Sawaya, Raymond; Heimberger, Amy B.

2010-01-01

121

Role of Macrophage Migration Inhibitory Factor in the Th2 Immune Response to Epicutaneous Sensitization  

PubMed Central

We examined the role of macrophage migration inhibitory factor (MIF) in the generation of the Th2 response using MIF-deficient mice in a model of epicutaneous sensitization (EC) to ovalbumin. Lymph node cells from sensitized MIF-deficient mice produce lower levels of Th2 cytokines after antigen challenge when compared to their wild-type counterparts. Sensitized mice lacking MIF show less pulmonary inflammation after intranasal antigen exposure. Mice deficient in CD74, the MIF receptor, also are unable to generate an inflammatory response to epicutaneous sensitization. Examination of the elicitation phase of the atopic response using DO11.1 OVA TCR transgenic animals shows that T cell proliferation and IL-2 production are strongly impaired in MIF-deficient T cells. This defect is most profound when both T cells and antigen presenting cells are lacking MIF. These data suggest that MIF is crucial both for the sensitization and the elicitation phases of a Th2-type immune response in allergic disease.

Das, Rituparna; Moss, Jeremy E.; Robinson, Eve; Roberts, Scott; Levy, Rebecca; Mizue, Yuka; Leng, Lin; McDonald, Courtney; Tigelaar, Robert E.; Herrick, Christina A.; Bucala, Richard

2013-01-01

122

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.

Rahat, Michal A.; Hemmerlein, Bernhard

2013-01-01

123

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.

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

2007-01-01

124

Role of TLR4 in ethanol effects on innate and adaptive immune responses in peritoneal macrophages  

Microsoft Academic Search

Toll-like receptors (TLRs) play an important role in the innate immune response and these receptors link innate and adaptive responses. We have reported that ethanol modulates TLR4 receptors by activating or inhibiting its response. However, the role of TLRs in the effects of ethanol on the innate and adaptive responses during acute or chronic treatment is presently unknown. Peritoneal macrophages

María Pascual; Sara Fernández-Lizarbe; Consuelo Guerri

2011-01-01

125

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...

126

Dual role of immune cells in the testis  

PubMed Central

The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs). Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium. Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-?, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis.

Perez, Cecilia V.; Theas, Maria S.; Jacobo, Patricia V.; Jarazo-Dietrich, Sabrina; Guazzone, Vanesa A.; Lustig, Livia

2013-01-01

127

Bromelain Activates Murine Macrophages and Natural Killer Cells in Vitro  

Microsoft Academic Search

The innate immune response is critical for effective immunity against most pathogens. In this study, we show that bromelain, a mixture of cysteine proteases, can enhance IFN-?-mediated nitric oxide and TNF? production by macrophages. Bromelain's effect was independent of endotoxin receptor activation and was not caused by direct modulation of IFN-? receptors. Instead, bromelain either enhanced or acted synergistically with

Christian R. Engwerda; Deborah Andrew; Michaela Murphy; Tracey L. Mynott

2001-01-01

128

Adiponectin Reduces Lipid Accumulation in Macrophage Foam Cells  

PubMed Central

Adiponectin is one of several, important metabolically active cytokines secreted from adipocytes. Low circulating levels of this adipokine have been associated epidemiologically with obesity, insulin resistance, type II diabetes, and cardiovascular disease. To determine if adiponectin can modulate lipid metabolism in macrophages, we expressed the adiponectin gene in human THP-1 macrophage foam cells using a lentiviral vector expression system and demonstrated that macrophages transduced with the adiponectin gene had decreased lipid accumulation compared with control macrophages transduced with the LacZ gene. Macrophages transduced with the adiponectin gene also exhibited decreased oxidized low-density lipoprotein (oxLDL) uptake and increased HDL-mediated cholesterol efflux. Additional studies suggest two potential mechanisms for the reduced lipid accumulation in these adiponectin-transduced macrophage foam cells. The first mechanism involves the PPAR? and LXR signaling pathways which up-regulate the expression of ABCA1 and promote lipid efflux from these cells. The second mechanism involves decreased lipid uptake and increased lipid hydrolysis which may result from decreased SR-AI and increased SR-BI and HSL gene activities in the transformed macrophage foam cells. We demonstrated also that the expression of two proatherogenic cytokines, MCP-1 and TNF?, were decreased in the adiponectin transduced macrophage foam cells. These results suggest that adiponectin may modulate multiple pathways of lipid metabolism in macrophages. Our studies provide new insights into potential mechanisms of adiponectin-mediated alterations in lipid metabolism and macrophage foam cell formation which may impact the development of atherosclerosis.

Tian, Ling; Luo, Nanlan; Klein, Richard L.; Chung, B Hong; Garvey, W. Timothy; Fu, Yuchang

2009-01-01

129

Transcutaneous immunization: T cell responses and boosting of existing immunity  

Microsoft Academic Search

Transcutaneous immunization (TCI) is a novel immunization strategy by which antigen and adjuvant are applied topically to intact, hydrated skin to induce potent antibody and cell-mediated immune responses specific for both the antigen and the adjuvant. Using tetanus toxoid as a model antigen, we examined the T cell response to tetanus toxoid after topical immunization with a variety of adjuvants.

Scott A Hammond; Deborah Walwender; Carl R Alving; Gregory M Glenn

2001-01-01

130

Regulatory role of periodontal ligament fibroblasts for innate immune cell function and differentiation.  

PubMed

Innate immunity is crucial for an effective host defense against pathogenic microorganisms in periodontal tissues. As periodontal ligament (PDL) cells synthesize immunomodulatory cytokines, the aim of this in vitro study was to investigate whether these cells can interact with innate immune cells. Resting and inflammatory primed (IL-1?, TNF-?, HMGB1) human PDL cells were co-cultured with human monocyte-derived dendritic cells or macrophages. Migration, phenotypic maturation and modulation of phagocytosis of Porphyromonas gingivalis by immune cells were investigated upon co-culture with PDL cells and/or their released soluble factors. PDL cells interacted with immune cells under both non-inflammatory and inflammatory conditions. Immune cell migration was significantly enhanced by co-culture with PDL cells, which also affected their phenotypic maturation both through cell-cell contact and through released soluble mediators. The dendritic cell maturation markers CD83 and CD86 were upregulated as much as both 'alternatively activated' M2 macrophage maturation markers CD23 and CD163. In contrast, the 'classically activated' M1 macrophage maturation marker CD64 was downregulated. Finally, PDL cells significantly enhanced the phagocytosis of Porphyromonas gingivalis by immune cells. Our experiments revealed that PDL cells are not only structural elements of the periodontium, but actively influence immune responses by interaction with innate immune cells. PMID:22436844

Konermann, Anna; Stabenow, Dirk; Knolle, Percy A; Held, Stefanie A E; Deschner, James; Jäger, Andreas

2012-03-21

131

Macrophage recognition of cells undergoing programmed cell death (apoptosis).  

PubMed Central

As a model for the recognition of effete cells by their viable neighbours. BALB/c mouse thymocytes were coincubated with isologous peritoneal macrophages. The macrophages bound preferentially to thymocytes undergoing apoptosis, a mode of death induced in these cells by treatment with the glucocorticoid hormone methyl-prednisolone. Binding occurred in the absence of serum and was inhibited by N,N'-diacetyl chitobiose, N-acetyl glucosamine and, to a lesser extent, by N-acetyl galactosamine and D-galactose. L-fucose, D-mannose and N-acetyl neuraminic acid had no effect. The results suggest the presence of lectin-like molecules on the surface of the macrophage that recognize changes in the cell-surface carbohydrate of the apoptotic cell. The pattern of inhibition of binding by monosaccharides differs from that of previously described endogenous mammalian lectins.

Duvall, E; Wyllie, A H; Morris, R G

1985-01-01

132

Mucosal macrophage subsets of the gut in HIV: decrease in antigen-presenting cell phenotype.  

PubMed Central

The effect of HIV infection on intestinal lamina propria macrophage subsets was investigated in 41 patients at various stages of HIV infection (asymptomatic HIV infection, n = 17; AIDS, n = 24). Duodenal biopsies taken from HIV patients at endoscopy were snap frozen and cryostat sections cut for immunohistochemical staining. MoAbs CD68 (EBM11, pan-macrophage marker), RFD1 (antigen-presenting cells) and RFD7 (mature phagocytic macrophages) were used to identify cell subsets using indirect immunoperoxidase or alkaline phosphatase. Double immunofluorescence using MoAbs to HIV proteins (p24, p17 and gp120) and RFD1 were used to identify HIV-infected antigen-presenting cells. Double immunofluorescence was also used to identify macrophages that expressed both RFD1 and RFD7 ('suppressor' macrophages). Intensity of HLA-DR expression in lamina propria cells was investigated using a MoAb to HLA-DR directly conjugated to glucose oxidase. The results show that there was no difference in overall density of macrophages, but there was a significant decrease in dendritic cells (RFD1+) in all clinical stages of HIV. There was no difference in the density of RFD7+ macrophages, nor was there a difference intensity of HLA-DR expression in lamina propria cells. Only four HIV-infected cells were positively identified in the 41 patients. This result suggests that the antigen-presenting arm of mucosal immune defences may be seriously compromised in HIV infection, and represents a further insult to mucosal immunity already impaired as a result of loss of CD4+ T lymphocytes. This may contribute to development of opportunist infection in the gut.

Lim, S G; Condez, A; Poulter, L W

1993-01-01

133

Human Uterine NK cells Interact with Uterine Macrophages via NKG2D upon stimulation with PAMPs  

PubMed Central

Problem The initiation of an immune response often involves the cooperation of various innate immune cells. In the human endometrium, uterine NK cells and uterine macrophages are present in significant numbers and in close proximity, yet how they cooperatively respond to infectious challenge is poorly understood. Method of study Primary autologous uterine NK cells and macrophages were co-cultured to determine functional interactions after stimulation with PAMPs. Results After stimulation by polyI:C, human uNK cells interact with autologous uterine macrophages and produce IFN-? in an NKG2D-dependent manner. Stimulated primary uterine macrophages upregulated the expression of MHC Class I Chain-related protein A (MICA), but expression of the cognate receptor NKG2D remained unchanged on uNK cells, even in the presence of cytokines. Conclusion This study demonstrates that the NKG2D-MICA interaction is an important molecular mechanism that is involved in the innate immune response to microbial signals in the human uterine endometrium.

Basu, Satarupa; Eriksson, Mikael; Pioli, Patricia A.; Conejo-Garcia, Jose; Mselle, Teddy F.; Yamamoto, Satoshi; Wira, Charles R.; Sentman, Charles L.

2010-01-01

134

Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization.  

PubMed

Complement receptor 1 (CR1) expressed on the surface of phagocytic cells binds complement-bound immune complexes (IC), playing an important role in the clearance of circulating IC. This receptor is critical to prevent accumulation of IC, which can contribute to inflammatory pathology. Accumulation of circulating IC is frequently observed during malaria, although the factors contributing to this accumulation are not clearly understood. We have observed that the surface expression of CR1 on monocytes/macrophages and B cells is strongly reduced in mice infected with Plasmodium yoelii, a rodent malaria model. Monocytes/macrophages from these infected mice present a specific inhibition of complement-mediated internalization of IC caused by the decreased CR1 expression. Accordingly, mice show accumulation of circulating IC and deposition of IC in the kidneys that inversely correlate with the decrease in CR1 surface expression. Our results indicate that malaria induces a significant decrease on surface CR1 expression in the monocyte/macrophage population that results in deficient internalization of IC by monocytes/macrophages. To determine whether this phenomenon is found in human malaria patients, we have analyzed 92 patients infected with either P. falciparum (22 patients) or P. vivax (70 patients) , the most prevalent human malaria parasites. The levels of surface CR1 on peripheral monocytes/macrophages and B cells of these patients show a significant decrease compared with uninfected control individuals in the same area. We propose that this decrease in CR1 plays an essential role in impaired IC clearance during malaria. PMID:23440418

Fernandez-Arias, Cristina; Lopez, Jean Pierre; Hernandez-Perez, Jean Nikolae; Bautista-Ojeda, Maria Dolores; Branch, Oralee; Rodriguez, Ana

2013-02-25

135

Purkinje Cell Association with Microglia\\/Macrophages in Degenerating Cerebellum of Multiple System Atrophy Patients  

Microsoft Academic Search

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease with unknown etiology, involving Parkinson's disease, Autonomic Failure, and Olivopontocerebellar Atrophy (OPCA). To define a possible relationship between phagocytic immune cells and loss of Purkinje cells in MSA\\/OPCA, we measured the incidence of microglial\\/macrophages in close association with Purkinje cells and\\/or their axons and dendrites. Using immunocytochemistry methods on cerebellar sections

Ashley A. McKinney; Charles F. Ide

2011-01-01

136

The role of immune-related myeloid cells in angiogenesis.  

PubMed

Macrophage function is not restricted to the innate and adaptive immune responses, but also includes host defence, wound healing, angiogenesis and homeostatic processes. Within the spectrum of macrophage activation there are two extremes: M1 classically activated macrophages which have a pro-inflammatory phenotype, and M2 alternatively activated macrophages which are pro-angiogenic and anti-inflammatory. An important property of macrophages is their plasticity to switch from one phenotype to the other and they can be defined in their polarisation state at any point between the two extremes. In order to determine what stage of activation macrophages are in, it is essential to profile various phenotypic markers for their identification. This review describes the angiogenic role for myeloid cells: circulating monocytes, Tie-2 expressing monocytes (TEMs), myeloid-derived suppressor cells (MDSCs), tumour associated macrophages (TAMs), and neutrophils. Each cell type is discussed by phenotype, roles within angiogenesis and possible targets as a cell therapy. In addition, we also refer to our own research on myeloid angiogenic cells (MACs), outlining their ability to induce angiogenesis and their similarities to alternatively activated M2 macrophages. MACs significantly contribute to vascular repair through paracrine mechanisms as they lack the capacity to differentiate into endothelial cells. Since MACs also retain plasticity, phenotypic changes can occur according to disease states and the surrounding microenvironment. This pro-angiogenic potential of MACs could be harnessed as a novel cellular therapy for the treatment of ischaemic diseases, such as diabetic retinopathy, hind limb ischaemia and myocardial infarction; however, caution needs to be taken when MACs are delivered into an inflammatory milieu. PMID:23932437

Chambers, Sarah E J; O'Neill, Christina L; O'Doherty, T Michelle; Medina, Reinhold J; Stitt, Alan W

2013-07-08

137

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. Copyright © 2013 John Wiley & Sons, Ltd. 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

2013-03-21

138

Emerging Role of Mast Cells and Macrophages in Cardiovascular and Metabolic Diseases  

PubMed Central

Mast cells are essential in allergic immune responses. Recent discoveries have revealed their direct participation in cardiovascular diseases and metabolic disorders. Although more sophisticated mechanisms are still unknown, data from animal studies suggest that mast cells act similarly to macrophages and other inflammatory cells and contribute to human diseases through cell–cell interactions and the release of proinflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. Reduced cardiovascular complications and improved metabolic symptoms in animals receiving over-the-counter antiallergy medications that stabilize mast cells open another era of mast cell biology and bring new hope to human patients suffering from these conditions.

Xu, Jia-Ming

2012-01-01

139

Candida albicans Killing by RAW 264.7 Mouse Macrophage Cells: Effects of Candida Genotype, Infection Ratios, and Gamma Interferon Treatment  

Microsoft Academic Search

Phagocytic cells such as neutrophils and macrophages are potential components of the immune defense that protects mammals against Candida albicans infection. We have tested the interaction between the mouse macrophage cell line RAW 264.7 and a variety of mutant strains of C. albicans. We used an end point dilution assay to monitor the killing of C. albicans at low multiplicities

A. Marcil; D. Harcus; D. Y. Thomas; M. Whiteway

2002-01-01

140

Immune protective mechanisms during pregnancy. I. Cell-mediated immunity against Listeria monocytogenes in pregnant mice.  

PubMed Central

Characteristics of protective mechanisms during pregnancy were investigated using neonatally thymectomized (NTx) and/or pregnant mice infected with sublethal doses of Listeria monocytogenes, of which the explosive growth at an early phase of 2 or 3 days after infection is prevented by non-immune macrophages, and complete elimination at a late phase from 4 to 10 days after infection is attributed to the augmented functions of macrophages in co-operation with lymphokine-producing sensitized T lymphocytes. Although in virgin control mice there was a gradual decline of bacteria from the day after infection, viable bacteria in pregnant mice showed an increase in number until Day 3. In such pregnant mice, carbon clearance was suppressed. Thus, the enhanced bacterial growth in pregnant mice within 3 days may be attributable to the suppressed functions of non-immune macrophages. Complete elimination of Listeria from Day 4 was observed in pregnant sham-operated mice as well as in non-pregnant and pregnant NTx mice. Twenty-four hour reaction of delayed-type in normal mice induced by sheep red blood cells (SRBC) in incomplete Freund's adjuvant (IFA) was not affected by pregnancy, while 48 hr reaction in mice immunized with SRBC in complete Freund's adjuvant (CFA) was suppressed by pregnancy. We have reported previously that macrophage migration inhibitory factor (MIF) was produced in the latter but not in the former, and that the tuberculin type of delayed hypersensitivity accompanied by MIF production scarcely participated in acquired resistance to Listeria. Effective elimination of Listeria in pregnant and/or NTx mice at a late phase may be attributable to the activity of cellular immunity comparable to 24 hr reaction. These results suggest that T cells showing a low degree of thymus dependency in the ontogenic development may be the major component required for acquired protective immunity against Listeria and may account for the protection in pregnant mice.

Shinomiya, N; Tsuru, S; Taniguchi, M; Fujisawa, H; Ikeda, M; Zinnaka, Y; Nomoto, K

1986-01-01

141

Candida albicans infection inhibits macrophage cell division and proliferation  

PubMed Central

The pathogenicity of the opportunistic human fungal pathogen Candida albicans depends on its ability to inhibit effective destruction by host phagocytes. Using live cell video microscopy, we show here for the first time that C. albicans inhibits cell division in macrophages undergoing mitosis. Inhibition of macrophage cell division is dependent on the ability of C. albicans to form hyphae, as it is rarely observed following phagocytosis of UV-killed or morphogenesis-defective mutant Candida. Interestingly, failed cell division following phagocytosis of hyphal C. albicans is surprisingly common, and leads to the formation of large multinuclear macrophages. This raises question as to whether inhibition of macrophage cell division is another virulence attribute of C. albicans or enables host macrophages to contain the pathogen.

Lewis, Leanne E.; Bain, Judith M.; Lowes, Christina; Gow, Neil A.R.; Erwig, Lars-Peter

2012-01-01

142

Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages.  

PubMed

ADAs play a pivotal role in regulating the level of adenosine, a signaling molecule controlling a variety of cellular responses by binding to and activating four ADRs. Two enzymes, ADA1 and ADA2, are known to possess ADA activity in humans. Although the structure of ADA1 and its role in lymphocytic activation have been known for a long time, the structure and function of ADA2, a member of ADGF, remain enigmatic. Here, we found that ADA2 is secreted by monocytes undergoing differentiation into macrophages or DCs and that it binds to the cell surface via proteoglycans and ADRs. We demonstrate that ADA1 and ADA2 increase the rate of proliferation of monocyte-activated CD4+ T cells independently of their catalytic activity. We also show that ADA2 induces T cell-dependent differentiation of monocytes into macrophages and stimulates macrophage proliferation. Our discovery of the growth factor-like activity of ADA2 explains clinical observations and suggests that this enzyme could be used as a drug candidate to modulate the immune responses during inflammation and cancer. PMID:20453107

Zavialov, Andrey V; Gracia, Eduard; Glaichenhaus, Nicolas; Franco, Rafael; Zavialov, Anton V; Lauvau, Grégoire

2010-05-07

143

Adipose-derived stromal cells: cytokine expression and immune cell contaminants.  

PubMed

The present method describes an immunoselection/depletion approach to isolate the native human adipose tissue-derived progenitor cells that are free from endothelial cells and immune cells by the use of magnetic nanobeads and microbeads coupled to antibodies. Moreover, methods to isolate and to analyse the distinct cell populations that constitute the microenvironment of the human adipose tissue progenitor cells, i.e. mature adipocytes, endothelial cells, and macrophages, are mentioned. PMID:21082401

Decaunes, Pauline; Estève, David; Zakaroff-Girard, Alexia; Sengenès, Coralie; Galitzky, Jean; Bouloumié, Anne

2011-01-01

144

Macrophage heterogeneity in lymphoid tissues.  

PubMed

Macrophages in lymphoid organs exhibit a wide variety of phenotypes and functions. These cells excel in the removal of apoptotic cells that arise during the generation of immune cells and are thereby essential for the prevention of auto-immune responses. In addition to this macrophages in the secondary lymphoid organs form an important barrier for spreading of infections by phagocytosis of pathogens and the activation of both innate and adaptive immune responses. Thus, the remarkable ability of macrophages to phagocytose and handle a wide range of self and non-self material and to produce immunomediators is effectively exploited within lymphoid organs to regulate immune activation. PMID:23579230

den Haan, Joke M M; Martinez-Pomares, Luisa

2013-04-12

145

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

2012-09-03

146

Role of macrophages in early protective immune responses induced by two vaccines against foot and mouth disease.  

PubMed

Foot and Mouth Disease (FMD) is an acute disease of cloven-hoofed species. We studied the protection and early immune response induced in the murine model by vaccines formulated with inactivated virus and two different adjuvants. The presence of IMS12802PR or ISA206VG adjuvants yielded protection against viral challenge at early times post vaccination and induced FMDV-specific, but non neutralizing, antibody titers. In vivo macrophage depletion in vaccinated mice severely decreased the protection levels after virus challenge, indicating a central role of this cell population in the response elicited by the vaccines. Accordingly, opsonophagocytosis of FITC-labelled virus was augmented in 802-FMDVi and 206-FMDVi vaccinated mice. These results demonstrate the ability of the studied adjuvants to enhance the protective responses of these inactivated vaccines without the increase in seroneutralizing antibodies and the main role of opsonization and phagocytosis in the early protective immune responses against FMD infection in the murine model. PMID:21878353

Quattrocchi, V; Langellotti, C; Pappalardo, J S; Olivera, V; Di Giacomo, S; van Rooijen, N; Mongini, C; Waldner, C; Zamorano, P I

2011-08-24

147

In vitro activation of rat neutrophils and alveolar macrophages with IgA and IgG immune complexes. Implications for immune complex-induced lung injury.  

PubMed Central

In the rat, both IgG and IgA immune complexes induce oxygen radical mediated lung injury that is partially complement-dependent. In vivo studies have suggested that the chief sources of oxygen radicals in IgG and IgA immune complex-induced lung injury are neutrophils and tissue macrophages, respectively. The current studies have been designed to provide additional insights into these two models of tissue injury. Preformed monoclonal IgG and IgA immune complexes stimulated dose-dependent O2-. and H2O2 production by alveolar macrophages. In contrast, neutrophils exhibited O2-. production and lysosomal enzyme secretion in response to IgG immune complexes, but not in response to IgA complexes. There is evidence that C5a significantly amplifies these responses. Purified human C5a enhanced the O2-. responses of neutrophils activated with IgG immune complexes and alveolar macrophages activated with either IgG or IgA immune complexes. Addition of C5a alone to neutrophils or alveolar macrophages had no direct stimulatory effect as measured by O2-. production. The observation that O2-. responses of immune complex-activated alveolar macrophages can be significantly enhanced by the presence of C5a and that C5a can also enhance O-2. responses of IgG immune complex-stimulated neutrophils suggests a potential amplification mechanism through which complement may participate in both IgG and IgA immune complex-induced lung injury. The present data corroborate in vivo studies which suggest that IgG immune complex lung injury is primarily neutrophil-mediated, whereas IgA complex lung injury is predominantly macrophage-mediated.

Warren, J. S.; Kunkel, S. L.; Johnson, K. J.; Ward, P. A.

1987-01-01

148

Comparative analysis of the interaction of Helicobacter pylori with human dendritic cells, macrophages, and monocytes.  

PubMed

Helicobacter pylori may cause chronic gastritis, gastric cancer, or lymphoma. Myeloid antigen-presenting cells (APCs) are most likely involved in the induction and expression of the underlying inflammatory responses. To study the interaction of human APC subsets with H. pylori, we infected monocytes, monocyte-derived dendritic cells (DCs), and monocyte-derived (classically activated; M1) macrophages with H. pylori and analyzed phenotypic alterations, cytokine secretion, phagocytosis, and immunostimulation. Since we detected CD163(+) (alternatively activated; M2) macrophages in gastric biopsy specimens from H. pylori-positive patients, we also included monocyte-derived M2 macrophages in the study. Upon H. pylori infection, monocytes secreted interleukin-1? (IL-1?), IL-6, IL-10, and IL-12p40 (partially secreted as IL-23) but not IL-12p70. Infected DCs became activated, as shown by the enhanced expression of CD25, CD80, CD83, PDL-1, and CCR7, and secreted IL-1?, IL-6, IL-10, IL-12p40, IL-12p70, and IL-23. However, infection led to significantly downregulated CD209 and suppressed the constitutive secretion of macrophage migration inhibitory factor (MIF). H. pylori-infected M1 macrophages upregulated CD14 and CD32, downregulated CD11b and HLA-DR, and secreted mainly IL-1?, IL-6, IL-10, IL-12p40, and IL-23. Activation of DCs and M1 macrophages correlated with increased capacity to induce T-cell proliferation and decreased phagocytosis of dextran. M2 macrophages upregulated CD14 and CD206 and secreted IL-10 but produced less of the proinflammatory cytokines than M1 macrophages. Thus, H. pylori affects the functions of human APC subsets differently, which may influence the course and the outcome of H. pylori infection. The suppression of MIF in DCs constitutes a novel immune evasion mechanism exploited by H. pylori. PMID:22615251

Fehlings, Michael; Drobbe, Lea; Moos, Verena; Renner Viveros, Pablo; Hagen, Jana; Beigier-Bompadre, Macarena; Pang, Ervinna; Belogolova, Elena; Churin, Yuri; Schneider, Thomas; Meyer, Thomas F; Aebischer, Toni; Ignatius, Ralf

2012-05-21

149

Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes  

PubMed Central

Helicobacter pylori may cause chronic gastritis, gastric cancer, or lymphoma. Myeloid antigen-presenting cells (APCs) are most likely involved in the induction and expression of the underlying inflammatory responses. To study the interaction of human APC subsets with H. pylori, we infected monocytes, monocyte-derived dendritic cells (DCs), and monocyte-derived (classically activated; M1) macrophages with H. pylori and analyzed phenotypic alterations, cytokine secretion, phagocytosis, and immunostimulation. Since we detected CD163+ (alternatively activated; M2) macrophages in gastric biopsy specimens from H. pylori-positive patients, we also included monocyte-derived M2 macrophages in the study. Upon H. pylori infection, monocytes secreted interleukin-1? (IL-1?), IL-6, IL-10, and IL-12p40 (partially secreted as IL-23) but not IL-12p70. Infected DCs became activated, as shown by the enhanced expression of CD25, CD80, CD83, PDL-1, and CCR7, and secreted IL-1?, IL-6, IL-10, IL-12p40, IL-12p70, and IL-23. However, infection led to significantly downregulated CD209 and suppressed the constitutive secretion of macrophage migration inhibitory factor (MIF). H. pylori-infected M1 macrophages upregulated CD14 and CD32, downregulated CD11b and HLA-DR, and secreted mainly IL-1?, IL-6, IL-10, IL-12p40, and IL-23. Activation of DCs and M1 macrophages correlated with increased capacity to induce T-cell proliferation and decreased phagocytosis of dextran. M2 macrophages upregulated CD14 and CD206 and secreted IL-10 but produced less of the proinflammatory cytokines than M1 macrophages. Thus, H. pylori affects the functions of human APC subsets differently, which may influence the course and the outcome of H. pylori infection. The suppression of MIF in DCs constitutes a novel immune evasion mechanism exploited by H. pylori.

Fehlings, Michael; Drobbe, Lea; Moos, Verena; Renner Viveros, Pablo; Hagen, Jana; Beigier-Bompadre, Macarena; Pang, Ervinna; Belogolova, Elena; Churin, Yuri; Schneider, Thomas; Meyer, Thomas F.; Aebischer, Toni

2012-01-01

150

Stem cells—meet immunity  

Microsoft Academic Search

The ability of stem cells to differentiate into various different cell types holds great promise for the treatment of irreversible\\u000a tissue damage that occurs in many debilitating conditions. With stem cell research advancing at a tremendous pace, it is becoming\\u000a clear that one of the greatest hurdles to successful stem cell-derived therapies is overcoming immune rejection of the transplant.\\u000a Although

Tracy S. P. Heng; Jarrod A. Dudakov; Danika M. P. Khong; Ann P. Chidgey; Richard L. Boyd

2009-01-01

151

The Synthetic Immunomodulator Murabutide Controls Human Immunodeficiency Virus Type 1 Replication at Multiple Levels in Macrophages and Dendritic Cells  

Microsoft Academic Search

Macrophages and dendritic cells are known to play an important role in the establishment and persistence of human immunodeficiency virus (HIV) infection. Besides antiretroviral therapy, several immune-based interventions are being evaluated with the aim of achieving better control of virus replication in reservoir cells. Murabutide is a safe synthetic immunomodulator presenting a capacity to enhance nonspecific resistance against viral infections

EDITH C. A. DARCISSAC; M.-J. Truong; J. Dewulf; Y. Mouton; A. Capron; G. M. Bahr

2000-01-01

152

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 ...

153

FERRITIN PARTICLES IN MACROPHAGES AND IN ASSOCIATED MAST CELLS  

PubMed Central

In a variety of tissues (lymph node and glandular stroma), mast cells have been found in close and often intimate association with macrophages containing numerous ferritin-like particles in their cytoplasm and within cytoplasmic vacuoles (siderosomes). Phagocytic vacuoles in a given macrophage differed markedly. Some contained abundant Prussian blue-reactive material and others contained periodic acid-Schiff reactive substance at the light microscope level, and ultrastructurally some were filled with ferritin particles and others were not. Ferritin-like particles have also been observed occasionally in the mast cells associated with macrophages and even within the matrix of some of the granules in these mast cells.

Simson, J. V.; Spicer, S. S.

1972-01-01

154

Granulocyte-macrophage colony-stimulating factor and the immune system  

Microsoft Academic Search

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional cytokine currently used for the reversal of\\u000a neutropenia associated with cytotoxic chemotherapy, bone marrow and haemopoietic stem cell transplantation. GM-CSF also modulates\\u000a the function of differentiated white blood cells. In the context of local inflammatory responses, GM-CSF stimulates macrophages\\u000a for antimicrobial and antitumor effects. GM-CSF further enhances healing and repair by its actions

Philip E. Tarr

1996-01-01

155

Recombinant YopJ induces apoptotic cell death in macrophages through TLR2.  

PubMed

Bacterial species evolved evasive maneuvers to bypass their recognition by the receptors primarily TLRs of the innate immune cells. We have reported that 3?g/ml of recombinant YopJ when provided extracellularly induced apoptosis in murine peritoneal macrophages in vitro. The present investigations demonstrate the role of TLR2 in apoptotic signals induced by rYopJ protein in murine peritoneal macrophages. The role of TLR2 in rYopJ induced macrophage apoptosis was shown by neutralization experiments and its co-immunoprecipitation with downstream molecule MyD88. The observed functional consequence of TLR2 neutralization were the inhibition of caspase-8 and caspase-3 activation, change in mitochondrial membrane potential (??m) and DNA fragmentation induced by rYopJ in macrophages. Further, rYopJ induced enhanced expression of IRAK-4, FADD, phosphorylation of I?B and p38 MAP kinase in macrophages. Pharmacological inhibitor of p38 MAP kinase and neutralization of TLR2 with neutralizing antibodies significantly inhibited the rYopJ induced caspases activation and DNA fragmentation, suggesting the possible involvement of TLR2 and p38 MAP kinase in rYopJ induced macrophages apoptosis. PMID:21131052

Pandey, Ashok Kumar; Sodhi, Ajit

2010-12-04

156

Immunogenic potential of irradiated lymphoma cells is enhanced by adjuvant immunotherapy and modulation of local macrophage populations.  

PubMed

The aim of this study was to assess the immunogenic potential of irradiated lymphoma cells in vivo and determine whether immunogenicity can be enhanced by modulation of the host immune system. Syngeneic murine lymphoma models irradiated ex vivo were used as an orthotopic cellular vaccination prior to challenge with viable tumor cells. We demonstrate that irradiated lymphoma cells are poorly immunogenic and that protective anti-tumor CD8 T-cell responses require the addition of immunostimulatory monoclonal antibody as an immune adjuvant, and increased frequency of antigen exposure by multiple vaccinations. Furthermore, we show the potential importance of macrophages in regulating immunogenicity of irradiated lymphoma cells and demonstrate that depletion of macrophages using clodronate-encapsulated liposomes considerably enhances primary vaccination efficacy in the presence of adjuvant anti-CD40 antibody. Our results demonstrate that the immunogenic potential of poorly immunogenic lymphoma cells dying after radiation therapy can be improved by modulation of the host immune system. PMID:23339450

Honeychurch, Jamie; Melis, Monique H M; Dovedi, Simon J; Mu, Lijun; Illidge, Timothy M

2013-02-18

157

Saliva of Rhipicephalus sanguineus tick impairs T cell proliferation and IFN-?-induced macrophage microbicidal activity  

Microsoft Academic Search

In this study, we investigated tick saliva effects on T cell proliferation, antigen presentation and IFN-?-induced macrophage activation, events which are associated with host immune defense mechanisms. Mice repeatedly infested with Rhipicephalus sanguineus ticks, similarly to dogs, did not develop resistance to further infestations. We determined that R. sanguineus tick saliva inhibited, in a dose-dependent manner, both Con-A and specific

Beatriz R Ferreira; João S Silva

1998-01-01

158

Macrophage involvement in the antitumoral effect of Nocardia-delipidated cell mitogen (NDCM).  

PubMed

Several immunomodulatory fractions derived from Nocardia have been found to inhibit the growth of several experimental tumors, including Lewis lung carcinoma (3LL). An involvement of both macrophages and lymphocytes in the antitumoral effect of Nocardia fractions has been suggested. The mechanism of the Nocardia delipidated Cell Mitogen (NDCM)-induced tumor-inhibiting effect was investigated further in the present study. Macrophages activated by NDCM exerted a cytotoxic effect on 3LL cells in vitro, indicating a direct influence of macrophages on the tumor cells. These results correlate with previous findings which showed a local accumulation of macrophages (but also lymphocytes) at the tumor site in NDCM-treated mice. In tumor-bearing mice--both treated and non-treated with NDCM--a splenomegaly due to a pronounced extramedullary hematopoiesis was seen. Concomitant with the gradual evolution of the extramedullary hematopoiesis in the red pulp, a depletion in white pulp component was observed, more pronounced in the control 3LL-bearing mice than in the 3LL-inoculated NDCM-treated animals. The disappearance of the lymphatic follicles in 3LL-bearing mice may be responsible for the failure to cope with the tumor. It is therefore possible that by delaying white pulp depletion, NDCM favors a better host defense against the tumor. Examination of lungs in 3LL-bearing mice treated by NDCM showed a rich infiltration of macrophages in the vicinity of isolated tumor cells, probably indicating a defensive role of NDCM-activated macrophages against metastatic spread of the tumor. Although the macrophage appears to be of major importance in the NDCM-induced host response against the tumor, other components of the immune system are probably system are probably also activated by the Nocardia fraction in defense against the neoplasm. PMID:1810422

Leibovici, J; Hoenig, S; Pinchassov, A; Barot-Ciorbaru, R

159

Dynamics of macrophage cell populations during murine pulmonary tuberculosis.  

PubMed

The influx of macrophages into the lungs is the major component of the granulomatous response to infection with Mycobacterium tuberculosis. In this investigation we used flow cytometric analysis to define macrophage populations entering the airways and lung tissues of infected mice. We demonstrate that by the judicious use of cell surface markers, especially CD11b and CD11c, several cell populations can be distinguished, allowing cell sorting and morphological definition. Primary populations of CD11b(-)/CD11c(+/high) were defined as alveolar macrophages, CD11b(high)/CD11c(+/high) as dendritic cells, and CD11b(+/mid)/CD11c(+/mid) as small macrophages or monocytes, and changes in the activation phenotype of these populations were followed over the early course of the infection. In further studies, these cell populations were compared with cells harvested during the chronic stage of the disease. During the chronic stage of infection, Ag-presenting class II molecules and activation markers were poorly expressed on dendritic, small macrophage, and monocyte cell populations, which may have important implications for the breakdown of the lesions during reactivation disease. This analytical approach may facilitate the further characterization of macrophage populations entering into the lung tissues and their relative contributions to host resistance to tuberculosis infection. PMID:12960339

Gonzalez-Juarrero, Mercedes; Shim, Tae Sun; Kipnis, Andre; Junqueira-Kipnis, Ana Paula; Orme, Ian M

2003-09-15

160

A Cell Permeable Peptide Inhibitor of NFAT Inhibits Macrophage Cytokine Expression and Ameliorates Experimental Colitis  

PubMed Central

Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-? induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10?/?) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10?/? mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases.

Kobayashi, Taku; Ryu, Hyungjin S.; Muhlbauer, Marcus; Li, Fengling; Jobin, Christian; Plevy, Scott E.

2012-01-01

161

Aminopeptidase N (CD13) Is Involved in Phagocytic Processes in Human Dendritic Cells and Macrophages  

PubMed Central

Aminopeptidase N (APN or CD13) is a membrane ectopeptidase expressed by many cell types, including myelomonocytic lineage cells: monocytes, macrophages, and dendritic cells. CD13 is known to regulate the biological activity of various peptides by proteolysis, and it has been proposed that CD13 also participates in several functions such as angiogenesis, cell adhesion, metastasis, and tumor invasion. We had previously reported that, in human monocytes and macrophages, CD13 modulates the phagocytosis mediated by receptors for the Fc portion of IgG antibodies (Fc?Rs). In this work, we analyzed the possible interaction of CD13 with other phagocytic receptors. We found out that the cross-linking of CD13 positively modulates the phagocytosis mediated by receptors of the innate immune system, since a significant increase in the phagocytosis of zymosan particles or heat-killed E. coli was observed when CD13 was cross-linked using anti-CD13 antibodies, in both macrophages and dendritic cells. Also, we observed that, during the phagocytosis of zymosan, CD13 redistributes and is internalized into the phagosome. These findings suggest that, besides its known functions, CD13 participates in phagocytic processes in dendritic cells and macrophages.

Villasenor-Cardoso, Monica I.; Frausto-Del-Rio, Dulce A.

2013-01-01

162

Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a CXCR2-dependent manner.  

PubMed

Infiltration of immune cells, specifically macrophages, into the tumor microenvironment has been linked to increased mammary tumor formation and progression. Activation of growth factor receptor signaling pathways within mammary epithelial cells, such as the fibroblast growth factor receptor 1 (FGFR1) pathway, induces recruitment of macrophages to the mammary epithelium. These macrophages promote increased epithelial cell proliferation and angiogenesis. However, the specific mechanisms by which these macrophages are regulated by the preneoplastic epithelial cells and the mechanisms of action of the macrophages within the developing FGFR1-driven tumor microenvironment remain unknown. In this study, we show that activation of inducible FGFR1 in mammary glands leads to decreased activity of the TGF?/Smad3 pathway in macrophages associated with early stage lesions. Further studies show that macrophages have increased expression of inflammatory chemokines that bind Cxcr2 following exposure to conditioned media from mammary epithelial and tumor cells in which the FGF pathway had been activated. The increase in these ligands is inhibited following activation of the TGF? pathway, suggesting that decreased TGF? signaling contributes to the upregulation of these chemokines. Using coculture studies, we further show that macrophages are capable of promoting epithelial and tumor cell migration and invasion through activation of Cxcr2. These results indicate that macrophage-derived Cxcr2 ligands may be important for promoting mammary tumor formation regulated by FGFR signaling. Furthermore, these results suggest that targeting Cxcr2 may represent a novel therapeutic strategy for breast cancers that are associated with high levels of infiltrating macrophages. PMID:22893608

Bohrer, Laura R; Schwertfeger, Kathryn L

2012-08-14

163

Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a Cxcr2-dependent manner  

PubMed Central

Infiltration of immune cells, specifically macrophages, into the tumor microenvironment has been linked to increased mammary tumor formation and progression. Activation of growth factor receptor signaling pathways within mammary epithelial cells, such as the fibroblast growth factor receptor 1 (FGFR1) pathway, induces recruitment of macrophages to the mammary epithelium. These macrophages promote increased epithelial cell proliferation and angiogenesis. However, the specific mechanisms by which these macrophages are regulated by the preneoplastic epithelial cells and the mechanisms of action of the macrophages within the developing FGFR1-driven tumor microenvironment remain unknown. In this study, we demonstrate that activation of inducible FGFR1 in mammary glands leads to decreased activity of the transforming growth factor beta (TGF?)/Smad3 pathway in macrophages associated with early stage lesions. Further studies demonstrate that macrophages have increased expression of inflammatory chemokines that bind Cxcr2 following exposure to conditioned media from mammary epithelial and tumor cells in which the FGF pathway had been activated. The increase in these ligands is inhibited following activation of the TGF? pathway, suggesting that decreased TGF? signaling contributes to the upregulation of these chemokines. Using co-culture studies, we further demonstrate that macrophages are capable of promoting epithelial and tumor cell migration and invasion through activation of Cxcr2. These results indicate that macrophage-derived Cxcr2 ligands may be important for promoting mammary tumor formation regulated by FGFR signaling. Furthermore, these results suggest that targeting Cxcr2 may represent a novel therapeutic strategy for breast cancers that are associated with high levels of infiltrating macrophages.

Bohrer, Laura R.; Schwertfeger, Kathryn L.

2013-01-01

164

Augmenting T helper cell immunity in cancer.  

PubMed

Cancer specific immunity elicited with vaccines has traditionally focused on the activation of the CD8 cytolytic T lymphocyte (CTL) often involving direct stimulation of immunity using HLA-class I binding peptide epitopes. Recently it has become clear that activation of the CTL immune effector arm alone is insufficient to mediate an anticancer response. A major problem is that CD8 T cells alone can not be sustained without the concomitant activation of CD4 T helper (Th) cells. In fact, it is now widely recognized that the Th cell regulates nearly all aspects of the adaptive immune response. In addition, Th cells can recruit the innate immune system during immune augmentation. Therefore, the focus of the immune response in cancer has shifted away from activating CTL immunity alone to activating Th cell immunity alone or concurrently with CTL. Evidence suggests that activating the Th cell is sufficient to get a complete adaptive immune response because, once activated, the Th cell will elicit endogenous CD8 T cell and humoral immunity. In this review, we discuss the role of the Th cell in the adaptive immune response to cancer, how peptides that are capable of activation of Th cells are identified, and the clinical translation of newly identified candidate Th cell peptide epitopes to human cancer specific vaccines. Over the next decade, studies should begin to further define how we can manipulate the Th immune effector arm to achieve effective antitumor immunity. PMID:16375690

Knutson, K L; Disis, M L

2005-12-01

165

Corynebacterium pyruviciproducens, as an immune modulator, can promote the activity of macrophages and up-regulate antibody response to particulate antigen.  

PubMed

Corynebacterium pyruviciproducens is a newly discovered Corynebacterium species with no known pathogenic components such as diphtheria toxin and tuberculostearic acid, and it has similar biological properties to Propionibacterium acnes, but its role of immunoregulation is drawing people's attention. In this work, based on the role of macrophages in removal of pathogenic bacteria as a primary scavenger and particulate antigen-presenting cell, the stimulation of macrophages by C. pyruviciproducens was analyzed through detecting the levels of cytokine secretion and expression of membrane molecules, and the effect of C. pyruviciproducens in promoting antibody response to sheep red blood cells (SRBC) in vivo was detected. In vitro, C. pyruviciproducens led to a sharp release of interleukin-6 and tumour necrosis factor-? and encouraged the activation of macrophages including enhanced expressions of MHC-II, CD40, CD80 and CD86. In vivo, it enhanced the humoral immune response against SRBC, a particulate antigen. These observations suggest that C. pyruviciproducens, as an immunoregulator, can promote the host humoral immune response to pathogenic microorganisms by regulating macrophage function. PMID:23239443

Tong, Jia; Han, Qingzhen; Wang, Shengjun; Su, Zhaoliang; Zheng, Dong; Shen, Pei; Xia, Sheng; Huang, Xinxiang; Shao, Qixiang; Xu, Huaxi

2012-11-01

166

The Consequence of Immune Suppressive Cells in the Use of Therapeutic Cancer Vaccines and Their Importance in Immune Monitoring  

PubMed Central

Evaluating the number, phenotypic characteristics, and function of immunosuppressive cells in the tumor microenvironment and peripheral blood could elucidate the antitumor immune response and provide information to evaluate the efficacy of cancer vaccines. Further studies are needed to evaluate the correlation between changes in immunosuppressive cells and clinical outcomes of patients in cancer vaccine clinical trials. This paper focuses on the role of T-regulatory cells, myeloid-derived suppressor cells, and tumor-associated macrophages in cancer and cancer immunotherapy and their role in immune monitoring.

Vergati, Matteo; Schlom, Jeffrey; Tsang, Kwong Y.

2011-01-01

167

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

168

NK cells and immune "memory".  

PubMed

Immunological memory is a hallmark of the adaptive immune system. However, the ability to remember and respond more robustly against a second encounter with the same pathogen has been described in organisms lacking T and B cells. Recently, NK cells have been shown to mediate Ag-specific recall responses in several different model systems. Although NK cells do not rearrange the genes encoding their activating receptors, NK cells experience a selective education process during development, undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e., memory cells), and mediate more efficacious secondary responses against previously encountered pathogens--all characteristics previously ascribed only to T and B cells in mammals. This review describes past findings leading up to these new discoveries, summarizes the evidence for and characteristics of NK cell memory, and discusses the attempts and future challenges to identify these long-lived memory NK cell populations in humans. PMID:21289313

Sun, Joseph C; Lopez-Verges, Sandra; Kim, Charles C; DeRisi, Joseph L; Lanier, Lewis L

2011-02-15

169

Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction.  

PubMed

Given the established anti-inflammatory properties of mesenchymal stromal cells (MSCs), we investigated their effect on inflammatory cell infiltration of ischemic cardiac tissue and cardiac function. We employed two types of MSCs, human bone marrow-derived (BM) MSCs and human umbilical cord perivascular cells in an experimental acute myocardial infarction (MI) model with the immune-deficient NOD/SCID gamma null mouse. Cells were infused 48 h after induction of MI and mice assessed 24 h later (72 h after MI) for bone marrow (BM), circulating and cardiac tissue-infiltrating monocytes/macrophages. We showed that in the presence of either MSC type, overall macrophage/monocyte levels were reduced, including pro-inflammatory M1-type macrophages, while the proportion of alternatively activated M2-type macrophages was significantly increased in the circulation and heart but not the BM. Moreover, we found decreased expression of IL-1? and IL-6, increased IL-10 expression and fewer apoptotic cardiomyocytes without changes in angiogenesis in the infarct area. Fractional shortening was enhanced 2 weeks after cell infusion but was similar to medium controls 16 weeks after MI. In vitro studies showed that BM MSCs increased the frequency of alternatively activated monocytes/macrophages, in part by MSC-mediated secretion of IL-10. Our data suggest a new mechanism for MSC-mediated enhancement of cardiac function, possibly via an IL-10 mediated switch from infiltration of pro-inflammatory to anti-inflammatory macrophages at the infarct site. Additional studies are warranted confirming the role of IL-10 and augmenting the anti-inflammatory effects of MSCs in cardiac regeneration. PMID:21901289

Dayan, Victor; Yannarelli, Gustavo; Billia, Filio; Filomeno, Paola; Wang, Xing-Hua; Davies, John E; Keating, Armand

2011-09-08

170

Differential susceptibility of bone marrow-derived dendritic cells and macrophages to productive infection with Listeria monocytogenes  

Microsoft Academic Search

Summary Dendritic cells (DC) are required for the immune response against Listeria monocytogenes and are permissive for infection in vivo and in vitro. However, it is unclear if DC provide a desirable intracellular niche for bacterial growth. To address this issue, we have compared the behaviour of L. monocytogenes in murine bone marrow-derived DC and macrophages (BMM). Similar to BMM,

Marlena M. Westcott; Curtis J. Henry; Anne S. Cook; Kenneth W. Grant; Elizabeth M. Hiltbold

2007-01-01

171

Estradiol reduces susceptibility of CD4+ T cells and macrophages to HIV-infection.  

PubMed

The magnitude of the HIV epidemic in women requires urgent efforts to find effective preventive methods. Even though sex hormones have been described to influence HIV infection in epidemiological studies and regulate different immune responses that may affect HIV infection, the direct role that female sex hormones play in altering the susceptibility of target cells to HIV-infection is largely unknown. Here we evaluated the direct effect of 17-?-estradiol (E2) and ethinyl estradiol (EE) in HIV-infection of CD4(+) T-cells and macrophages. Purified CD4(+) T-cells and monocyte-derived macrophages were generated in vitro from peripheral blood and infected with R5 and X4 viruses. Treatment of CD4(+) T-cells and macrophages with E2 prior to viral challenge reduced their susceptibility to HIV infection in a dose-dependent manner. Addition of E2 2 h after viral challenge however did not result in reduced infection. In contrast, EE reduced infection in macrophages to a lesser extent than E2 and had no effect on CD4(+) T-cell infection. Reduction of HIV-infection induced by E2 in CD4(+) T-cells was not due to CCR5 down-regulation, but was an entry-mediated mechanism since infection with VSV-G pseudotyped HIV was not modified by E2. In macrophages, despite the lack of an effect of E2 on CCR5 expression, E2-treatment reduced viral entry 2 h after challenge and increased MIP-1? secretion. These results demonstrate the direct effect of E2 on susceptibility of HIV-target cells to infection and indicate that inhibition of target cell infection involves cell-entry related mechanisms. PMID:23614015

Rodriguez-Garcia, Marta; Biswas, Nabanita; Patel, Mickey V; Barr, Fiona D; Crist, Sarah G; Ochsenbauer, Christina; Fahey, John V; Wira, Charles R

2013-04-17

172

Estradiol Reduces Susceptibility of CD4+ T Cells and Macrophages to HIV-Infection  

PubMed Central

The magnitude of the HIV epidemic in women requires urgent efforts to find effective preventive methods. Even though sex hormones have been described to influence HIV infection in epidemiological studies and regulate different immune responses that may affect HIV infection, the direct role that female sex hormones play in altering the susceptibility of target cells to HIV-infection is largely unknown. Here we evaluated the direct effect of 17-?-estradiol (E2) and ethinyl estradiol (EE) in HIV-infection of CD4+ T-cells and macrophages. Purified CD4+ T-cells and monocyte-derived macrophages were generated in vitro from peripheral blood and infected with R5 and X4 viruses. Treatment of CD4+ T-cells and macrophages with E2 prior to viral challenge reduced their susceptibility to HIV infection in a dose-dependent manner. Addition of E2 2 h after viral challenge however did not result in reduced infection. In contrast, EE reduced infection in macrophages to a lesser extent than E2 and had no effect on CD4+ T-cell infection. Reduction of HIV-infection induced by E2 in CD4+ T-cells was not due to CCR5 down-regulation, but was an entry-mediated mechanism since infection with VSV-G pseudotyped HIV was not modified by E2. In macrophages, despite the lack of an effect of E2 on CCR5 expression, E2–treatment reduced viral entry 2 h after challenge and increased MIP-1? secretion. These results demonstrate the direct effect of E2 on susceptibility of HIV-target cells to infection and indicate that inhibition of target cell infection involves cell-entry related mechanisms.

Rodriguez-Garcia, Marta; Biswas, Nabanita; Patel, Mickey V.; Barr, Fiona D.; Crist, Sarah G.; Ochsenbauer, Christina; Fahey, John V.; Wira, Charles R.

2013-01-01

173

Effects of marginal iron overload on iron homeostasis and immune function in alveolar macrophages isolated from pregnant and normal rats  

Microsoft Academic Search

The effects of changes in macrophage iron status, induced by single or multiple iron injections, iron depletion or pregnancy,\\u000a on both immune function and mRNA expression of genes involved in iron influx and egress have been evaluated. Macrophages isolated\\u000a from iron deficient rats, or pregnant rats at day 21 of gestation, either supplemented with a single dose of iron dextran,

Roberta J. Ward; Stephanie Wilmet; Rachida Legssyer; Daniel Leroy; Louise Toussaint; Robert R. Crichton; Christophe Pierreux; Louis Hue; Jacques Piette; Surjit Kaila Srai; Nita Solanky; Dominique Klein; Karl Summer

2009-01-01

174

Intermediary role of macrophages in the passage of suppressor signals between T-cell subsets  

PubMed Central

We have examined the ability of macrophages (Mphi) to transmit T-cell derived suppressor signals to other T cells. The suppressor signal studied is an antigen-specific factor which suppresses the ability of adoptively transferred, sensitized lymphocytes to express contact hypersensitivity in normal recipients. We have found that this factor binds to peritoneal exudate Mphi via cell surface structures which can be blocked with heat-aggregated gamma globulin. Dead (HK) Mphi bind the factor but fail to present it in a functional way to assay (immune) T cells, whereas live (L) Mphi perform both functions. Further, L Mphi can retrieve the factor in an active form from the surfaces of HK Mphi. Based on these and other findings (1-5), we discuss the possibility that Mphi may play as important a role in presenting T-cell communication signals to the cells of the immune system as they do in presenting antigen.

1978-01-01

175

Adrenergic modulation of immune cells: an update.  

PubMed

Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents. PMID:22160285

Marino, Franca; Cosentino, Marco

2011-12-08

176

Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated pathogen sensing and innate immunity  

PubMed Central

Recognition of pathogen-associated molecular patterns by innate immune receptors is essential for host defense responses. Although extracellular stress proteins are considered as indicators of the stressful conditions (e.g., infection or cell injury), the exact roles of these molecules in the extracellular milieu remain less defined. We found that glucose-regulated protein 170 (Grp170), the largest stress protein and molecular chaperone, is highly efficient in binding CpG oligodeoxynucleotides (CpG-ODN), the microbial DNA mimetic sensed by toll-like receptor 9 (TLR9). Extracellular Grp170 markedly potentiates the endocytosis and internalization of CpG-ODN by mouse bone marrow-derived macrophages and directly interacts with endosomal TLR9 on cell entry. These molecular collaborations result in the synergistic activation of the MyD88-dependent signaling and enhanced production of proinflammatory cytokines and nitric oxide in mouse primary macrophages as well as human THP-1 monocyte-derived macrophages, suggesting that Grp170 released from injured cells facilitates the sensing of pathogen-associated “danger” signals by intracellular receptors. This CpG-ODN chaperone complex-promoted innate immunity confers increased resistance in mice to infection of Listeria monocytogenes compared with CpG-ODN treatment alone. Our studies reveal a previously unrecognized attribute of Grp170 as a superior DNA-binding chaperone capable of amplifying TLR9 activation on pathogen recognition, which provides a conceptual advance in understanding the dynamics of ancient chaperoning functions inside and outside the cell.—Zuo, D., Yu, X., Guo, C., Yi, H., Chen, X., Conrad, D. H., Guo, T. L., Chen, Z., Fisher, P. B., Subjeck, J. R., Wang, X.-Y. Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated pathogen sensing and innate immunity.

Zuo, Daming; Yu, Xiaofei; Guo, Chunqing; Yi, Huanfa; Chen, Xing; Conrad, Daniel H.; Guo, Tai L.; Chen, Zhengliang; Fisher, Paul B.; Subjeck, John R.; Wang, Xiang-Yang

2012-01-01

177

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

PubMed

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

2013-05-20

178

Modulation of macrophage and B cell function by glycosaminoglycans  

Microsoft Academic Search

There is increasing evidence that the behavior of antigen-presenting cells may be regu- lated, in part, by the surrounding microenviron- ment. Components of the microenvironment of solid tissues that might influence antigen-presenting cell functions include glycosaminoglycans. We pre- viously showed that heparan sulfate glycosaminogly- cans activate macrophages, leading to profound alterations in T cell responses. Here we demon- strate the

Lucile E. Wrenshall; R. Brian Stevens; Frank B. Cerra; Jeffrey L. Platt

1999-01-01

179

Evasion of Innate Immune Responses: Evidence for Mannose Binding Lectin Inhibition of Tumor Necrosis Factor Alpha Production by Macrophages in Response to Blastomyces dermatitidis  

Microsoft Academic Search

Serum factors, including mannose binding lectins (MBL), influence innate responses to microbes. Little is known about the effects of serum factors or MBL on the interaction of Blastomyces dermatitidis ,a pulmonary fungal pathogen, with macrophages or on tumor necrosis factor alpha (TNF-) production. Since macrophage production of TNF- is an important innate immune response, we examined a mouse peritoneal macrophage

Adi Koneti; Michael J. Linke; Elmer Brummer; David A. Stevens

2008-01-01

180

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

Microsoft Academic Search

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

Nobuto Yamamoto; Venkateswara R Naraparaju

1998-01-01

181

Formation and some cytophysiological characteristics of polynuclear macrophages in primary cultures of peritoneal cells.  

PubMed

We studied the formation and cytophysiological characteristics of polynuclear macrophages in primary cultures of peritoneal cells from C57Bl/6 mice. Production of reactive oxygen species and phagocytic activity in polynuclear macrophages were higher than in mononuclear macrophages. The formation of polynuclear macrophages in cultures of peritoneal cells is realized via amitosis. PMID:19513400

Arkhipov, S A; Shkurupiy, V A; Ijine, D A; Ignatovich, N V; Akhromenko, E S; Arkhipova, V V

2008-12-01

182

Autoreactive preplasma cells break tolerance in the absence of regulation by dendritic cells and macrophages.  

PubMed

The ability to induce Ab responses to pathogens while maintaining the quiescence of autoreactive cells is an important aspect of immune tolerance. During activation of TLR4, dendritic cells (DCs) and macrophages (MFs) repress autoantibody production through their secretion of IL-6 and soluble CD40L (sCD40L). These soluble mediators selectively repress B cells chronically exposed to Ag, but not naive cells, suggesting a means to maintain tolerance during TLR4 stimulation, yet allow immunity. In this study, we identify TNF-? as a third repressive factor, which together with IL-6 and CD40L account for nearly all the repression conferred by DCs and MFs. Similar to IL-6 and sCD40L, TNF-? did not alter B cell proliferation or survival. Instead, it reduced the number of Ab-secreting cells. To address whether the soluble mediators secreted by DCs and MFs functioned in vivo, we generated mice lacking IL-6, CD40L, and TNF-?. Compared to wild-type mice, these mice showed prolonged anti-nuclear Ab responses following TLR4 stimulation. Furthermore, adoptive transfer of autoreactive B cells into chimeric IL-6(-/-) × CD40L(-/-) × TNF-?(-/-) mice showed that preplasma cells secreted autoantibodies independent of germinal center formation or extrafollicular foci. These data indicate that in the absence of genetic predisposition to autoimmunity, loss of endogenous IL-6, CD40L, and TNF-? promotes autoantibody secretion during TLR4 stimulation. PMID:22675201

Gilbert, Mileka R; Wagner, Nikki J; Jones, Shannon Z; Wisz, Amanda B; Roques, Jose R; Krum, Kristen N; Lee, Sang-Ryul; Nickeleit, Volker; Hulbert, Chrys; Thomas, James W; Gauld, Stephen B; Vilen, Barbara J

2012-06-06

183

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.

Dugast, A-S; Vanhove, B

2009-01-01

184

NKT cells — conductors of tumor immunity?  

Microsoft Academic Search

NKT cells are key players in the regulation of antitumor immunity, particularly in experimental models of tumor immunotherapy, such as IL-12 or ?-galactosylceramide administration. They may also operate in natural antitumor immunity. NKT cells are best known for their immunosuppressive functions; however, NKT cells interact with a range of other cell types (particularly dendritic cells and NK cells) and the

Mark J Smyth; Nadine Y Crowe; Yoshihiro Hayakawa; Kazuyoshi Takeda; Hideo Yagita; Dale I Godfrey

2002-01-01

185

Structurally distinct phosphatases CD45 and CD148 both regulate B cell and macrophage immunoreceptor signaling  

PubMed Central

The receptor-type protein tyrosine phosphatase (RPTP) CD148 is thought to have an inhibitory function in signaling and proliferation in non-hematopoietic cells. However, its role in the immune system has not been thoroughly studied. Our analysis of CD148 loss of function mice suggests that CD148 has a positive regulatory function in B-cells and macrophages, similar to the role of CD45 as a positive regulator of Src-family kinases (SFKs). Analysis of CD148/CD45 doubly-deficient B cells and macrophages revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SFKs accompanied by substantial alterations in B and myeloid lineage development and defective immunoreceptor signaling. These findings suggest the C-terminal tyrosine of SFKs is a common substrate for both CD148 and CD45 phosphatases and that a reassessment of the function of CD45 in the B and myeloid lineages is warranted.

Zhu, Jing W.; Brdicka, Tomas; Katsumoto, Tamiko R.; Lin, Joseph; Weiss, Arthur

2008-01-01

186

Therapeutic Immunization with HIV1 Tat Reduces Immune Activation and Loss of Regulatory T-Cells and Improves Immune Function in Subjects on HAART  

Microsoft Academic Search

Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat

Barbara Ensoli; Stefania Bellino; Antonella Tripiciano; Olimpia Longo; Vittorio Francavilla; Simone Marcotullio; Aurelio Cafaro; Orietta Picconi; Giovanni Paniccia; Arianna Scoglio; Angela Arancio; Cristina Ariola; Maria J. Ruiz Alvarez; Massimo Campagna; Donato Scaramuzzi; Cristina Iori; Roberto Esposito; Cristina Mussini; Florio Ghinelli; Laura Sighinolfi; Guido Palamara; Alessandra Latini; Gioacchino Angarano; Nicoletta Ladisa; Fabrizio Soscia; Vito S. Mercurio; Adriano Lazzarin; Giuseppe Tambussi; Raffaele Visintini; Francesco Mazzotta; Massimo di Pietro; Massimo Galli; Stefano Rusconi; Giampiero Carosi; Carlo Torti; Giovanni di Perri; Stefano Bonora; Fabrizio Ensoli; Enrico Garaci; Kim J. Hasenkrug

2010-01-01

187

Induction of a Potential Paracrine Angiogenic Loop between Human THP1 Macrophages and Human Microvascular Endothelial Cells during Bartonella henselae Infection  

Microsoft Academic Search

Bartonella henselae is responsible for various disease syndromes that loosely correlate with the immune sta- tus of the host. In the immunocompromised individual, B. henselae-induced angiogenesis, or bacillary angio- matosis, is characterized by vascular proliferative lesions similar to those in Kaposi's sarcoma. We hypothesize that B. henselae-mediated interaction with immune cells, namely, macrophages, induces potential angiogenic growth factors and cytokines

Sandra I. Resto-Ruiz; Michael Schmiederer; Debra Sweger; Catherine Newton; Thomas W. Klein; Herman Friedman; Burt E. Anderson

2002-01-01

188

NFIL3 Is a Regulator of IL-12 p40 in Macrophages and Mucosal Immunity  

PubMed Central

Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b+ lamina propria mononuclear cells from Nfil3?/? mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14+ lamina propria mononuclear cells from Crohn’s disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10?/? mice transitioned from germ-free to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases.

Kobayashi, Taku; Matsuoka, Katsuyoshi; Sheikh, Shehzad Z.; Elloumi, Houda Z.; Kamada, Nobuhiko; Hisamatsu, Tadakazu; Hansen, Jonathan J.; Doty, Kevin R.; Pope, Scott D.; Smale, Stephen T.; Hibi, Toshifumi; Rothman, Paul B.; Kashiwada, Masaki; Plevy, Scott E.

2011-01-01

189

CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of Macrophages  

PubMed Central

Summary During breast cancer development, increased presence of leukocytes in neoplastic stroma parallels disease progression; however, the functional significance of leukocytes in regulating protumor versus antitumor immunity in the breast remains poorly understood. Utilizing the MMTV-PyMT model of mammary carcinogenesis, we demonstrate that IL-4-expressing CD4+ T lymphocytes indirectly promote invasion and subsequent metastasis of mammary adenocarcinomas by directly regulating the phenotype and effector function of tumor-associated CD11b+Gr1-F4/80+ macrophages that in turn enhance metastasis through activation of epidermal growth factor receptor signaling in malignant mammary epithelial cells. Together, these data indicate that antitumor acquired immune programs can be usurped in protumor microenvironments and instead promote malignancy by engaging cellular components of the innate immune system functionally involved in regulating epithelial cell behavior.

DeNardo, David G.; Barreto, Jairo B.; Andreu, Pauline; Vasquez, Lesley; Tawfik, David; Kolhatkar, Nikita; Coussens, Lisa M.

2009-01-01

190

Phenotypic and Functional Heterogeneity of Macrophages and Dendritic Cell Subsets in the Healthy and Atherosclerosis-Prone Aorta  

PubMed Central

Atherosclerosis continues to be the leading cause of cardiovascular disease. Development of atherosclerosis depends on chronic inflammation in the aorta and multiple immune cells are involved in this process. Importantly, resident macrophages and dendritic cells (DCs) are present within the healthy aorta, but the functions of these cells remain poorly characterized. Local inflammation within the aortic wall promotes the recruitment of monocytes and DC precursors to the aorta and micro-environmental factors direct the differentiation of these emigrated cells into multiple subsets of macrophages and DCs. Recent data suggest that several populations of macrophages and DCs can co-exist within the aorta. Although the functions of M1, M2, Mox, and M4 macrophages are well characterized in vitro, there is a limited set of data on the role of these populations in atherogenesis in vivo. Recent studies on the origin and the potential role of aortic DCs provide novel insights into the biology of aortic DC subsets and prospective mechanisms of the immune response in atherosclerosis. This review integrates the results of experiments analyzing heterogeneity of DCs and macrophage subsets in healthy and diseased vessels and briefly discusses the known and potential functions of these cells in atherogenesis.

Butcher, Matthew J.; Galkina, Elena V.

2012-01-01

191

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

PubMed

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

2012-12-28

192

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.

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

2012-01-01

193

Idiopathic pulmonary fibrosis: can cell mediated immunity markers predict clinical outcome?  

Microsoft Academic Search

Most of the cells found in lung parenchyma in patients with idiopathic pulmonary fibrosis are activated T lymphocytes and macrophages. The serum levels of three markers of cell mediated immunity were measured in 20 patients with idiopathic pulmonary fibrosis, in 20 normal subjects and in 12 patients with sarcoidosis to evaluate their clinical and prognostic significance in idiopathic pulmonary fibrosis.

R Meliconi; E Lalli; R M Borzì; C Sturani; V Galavotti; G Gunella; R Miniero; A Facchini; G Gasbarrini

1990-01-01

194

Hydrogen peroxide produced by oral Streptococci induces macrophage cell death.  

PubMed

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

2013-05-03

195

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.

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

2013-01-01

196

Macrophages Are Critical for Cross-Protective Immunity Conferred by Babesia microti against Babesia rodhaini Infection in Mice  

PubMed Central

Although primary infection of mice with Babesia microti has been shown to protect mice against subsequent lethal infection by Babesia rodhaini, the mechanism behind the cross-protection is unknown. To unravel this mechanism, we investigated the influence of primary infection of mice with nonlethal B. microti using different time courses on the outcome of subsequent lethal B. rodhaini infection. Simultaneous infections of mice with these parasites resulted in rapid increases in parasitemia, with 100% mortality in BALB/c mice, as observed with control mice infected with B. rodhaini alone. In contrast, mice with acute, resolving, and chronic-phase B. microti infections were completely protected against B. rodhaini, resulting in low parasitemia and no mortalities. Mice immunized with dead B. microti were not protected from B. rodhaini infection, although high antibody responses were induced. Interestingly, the protected mice had significantly decreased levels of antibody response, cytokines (including gamma interferon [IFN-?], interleukin-2 [IL-2], IL-8, IL-10, and IL-12), and nitric oxide levels after infection with B. rodhaini. SCID mice and IFN-?-deficient mice with chronic B. microti infections demonstrated protective responses comparable to those of immunocompetent mice. Likewise, in vivo NK cell depletion did not significantly impair the protective responses. Conversely, macrophage depletion resulted in increased susceptibility to B. rodhaini infection associated with changes in their antibody and cytokines profiles, indicating that macrophages contribute to the protection against this challenge infection. We conclude that future development of vaccines against Babesia should include a strategy that enhances the appropriate activation of macrophages.

Li, Yan; Terkawi, Mohamad Alaa; Nishikawa, Yoshifumi; Aboge, Gabriel Oluga; Luo, Yuzi; Ooka, Hideo; Goo, Youn-Kyoung; Yu, Longzheng; Cao, Shinuo; Sun, Yongfeng; Yamagishi, Junya; Masatani, Tatsunori; Yokoyama, Naoaki; Igarashi, Ikuo

2012-01-01

197

Macrophages are critical for cross-protective immunity conferred by Babesia microti against Babesia rodhaini infection in mice.  

PubMed

Although primary infection of mice with Babesia microti has been shown to protect mice against subsequent lethal infection by Babesia rodhaini, the mechanism behind the cross-protection is unknown. To unravel this mechanism, we investigated the influence of primary infection of mice with nonlethal B. microti using different time courses on the outcome of subsequent lethal B. rodhaini infection. Simultaneous infections of mice with these parasites resulted in rapid increases in parasitemia, with 100% mortality in BALB/c mice, as observed with control mice infected with B. rodhaini alone. In contrast, mice with acute, resolving, and chronic-phase B. microti infections were completely protected against B. rodhaini, resulting in low parasitemia and no mortalities. Mice immunized with dead B. microti were not protected from B. rodhaini infection, although high antibody responses were induced. Interestingly, the protected mice had significantly decreased levels of antibody response, cytokines (including gamma interferon [IFN-?], interleukin-2 [IL-2], IL-8, IL-10, and IL-12), and nitric oxide levels after infection with B. rodhaini. SCID mice and IFN-?-deficient mice with chronic B. microti infections demonstrated protective responses comparable to those of immunocompetent mice. Likewise, in vivo NK cell depletion did not significantly impair the protective responses. Conversely, macrophage depletion resulted in increased susceptibility to B. rodhaini infection associated with changes in their antibody and cytokines profiles, indicating that macrophages contribute to the protection against this challenge infection. We conclude that future development of vaccines against Babesia should include a strategy that enhances the appropriate activation of macrophages. PMID:22064713

Li, Yan; Terkawi, Mohamad Alaa; Nishikawa, Yoshifumi; Aboge, Gabriel Oluga; Luo, Yuzi; Ooka, Hideo; Goo, Youn-Kyoung; Yu, Longzheng; Cao, Shinuo; Sun, Yongfeng; Yamagishi, Junya; Masatani, Tatsunori; Yokoyama, Naoaki; Igarashi, Ikuo; Xuan, Xuenan

2011-11-07

198

Identification of macrophage cell-surface binding sites for cationized bovine serum albumin.  

PubMed

Autoimmune diseases are characterized by the presence of autoantibodies often restricted to host proteins exhibiting charge rich domains. Charged polypeptides elicit strong immune responses, and cationized bovine serum albumin and other cationic proteins are significantly more immunogenic than their less charged counterparts. These phenomena may involve enhanced protein uptake by macrophages, resulting in greater processing and presentation of antigenic peptide-MHC complexes to T-cells. We compared macrophage cell-surface binding and uptake of native and cationized bovine serum albumin. Specific binding of [125I]cationized bovine serum albumin to THP-1 macrophages in vitro was 11-16 fold greater than for native albumin. Half-maximal inhibition of [125I]cationized albumin binding was observed at 10-7M ligand. The specificity of [125I]cationized bovine serum albumin binding and uptake was further studied in terms of competitive inhibition of proteolysis by proteins of varying charge content. Cationized bovine serum albumin, but not native albumin, inhibited proteolysis of [125I]cBSA. Calf thymus histones also inhibited cBSA degradation. High concentration of myelin basic protein was moderately effective at blocking cBSA degradation, while myoglobin and beta lactalbumin showed no inhibition. These results indicate that specific cell-surface binding sites which occur on macrophages may mediate selective uptake of certain proteins with highly charged domains including some autoantigens. PMID:1721810

Dohlman, J G; Pillion, D J; Rokeach, L A; Ramprasad, M P

1991-12-16

199

Bacillus anthracis Spores Stimulate Cytokine and Chemokine Innate Immune Responses in Human Alveolar Macrophages through Multiple Mitogen-Activated Protein Kinase Pathways  

Microsoft Academic Search

Contact with the human alveolar macrophage plays a key role in the innate immune response to Bacillus anthracis spores. Because there is a significant delay between the initial contact of the spore with the host and clinical evidence of disease, there appears to be temporary containment of the pathogen by the innate immune system. Therefore, the early macrophage response to

Kaushik Chakrabarty; Wenxin Wu; J. Leland Booth; Elizabeth S. Duggan; K. Mark Coggeshall; Jordan P. Metcalf

2006-01-01

200

The Identification of Lung Macrophages, Peritoneal Macrophages, and Type II Alveolar Lung Epithelial Cells by Antisera Against Cell-Specific Differentiation Antigens.  

National Technical Information Service (NTIS)

Rabbit antisera was successfully developed for the immunologic identification of lung macrophages and for comparative antigenicity studies against peritoneal macrophages. The antisera were raised against cell specific differentiation antigens of mice. Ant...

A. K. Szakal

1977-01-01

201

An essential role of macrophage inflammatory protein 1alpha/CCL3 on the expression of host's innate immunities against infectious complications.  

PubMed

Sepsis was induced by well-controlled cecal ligation and puncture (CLP) in macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3 knockout (CCL3(-/-)) and severe combined immunodeficiency (SCID) mice. CCL3(-/-) mice and their littermates (CCL3(+/+) mice) treated with anti-CCL3 monoclonal antibodies were susceptible (0-20% survival) to CLP-induced sepsis, and CCL3(-/-) mice supplemented with recombinant (r)CCL3 (250 ng/mouse) and CCL3(+/+) mice were resistant (70-80% survival). The resistance of SCID mice to CLP was markedly improved by the rCCL3 administration (88% survival), and SCID mice treated with saline were shown to be middling resistant to the same CLP (45% survival). However, the resistance of SCID-M mice (SCID mice depleted of the macrophage function) to CLP was not improved by the rCCL3 administration (11% survival), and 41% of SCID-M mice reconstituted with normal peritoneal macrophages and 79% of SCID-M mice inoculated with CCL3-treated peritoneal macrophages survived. In addition, the resistance of SCID-MN mice (SCID mice depleted of functional macrophages and neutrophils) to CLP was improved by the inoculation of CCL3-treated macrophages (78% survival), and all of SCID-MN mice inoculated with CCL3-treated neutrophils died. CCL3 is shown to be essential to the host resistance against bacterial sepsis. Macrophages but not neutrophils are highlighted as the major effector cells when protective innate immunities against sepsis are improved by CCL3. PMID:12488501

Takahashi, Hitoshi; Tashiro, Tsuguhiko; Miyazaki, Masaru; Kobayashi, Makiko; Pollard, Richard B; Suzuki, Fujio

2002-12-01

202

The role of macrophage cell death in tuberculosis  

Microsoft Academic Search

Studies of host responses to infection have traditionally focused on the direct antimicrobial activity of effector molecules (antibodies, complement, defensins, reactive oxygen and nitrogen intermediates) and immunocytes (macrophages, lymphocytes, and neutrophils among others). The discovery of the systems for programmed cell death of eukaryotic cells has revealed a unique role for this process in the complex interplay between microorganisms and

Hardy Kornfeld; Giorgio Mancino; Vittorio Colizzi

1999-01-01

203

Alveolar macrophage kineticsand multinucleatedgiant cell formation after lung injury  

Microsoft Academic Search

Multmucleated giant cells (MGC) are a prominent feature of some chronic inflammatory states in the lung. These cells are formed by macro- phage fusion, but how this process relates to the kinetics of alveolar macrophage (AM) production and proliferation is not clear. In this serial study, we compare AM kinetics and MGC formation after in- stilling carbon, silica, asbestos, bleomycin,

H. Prieditis; I. Y. A. Adamson

204

Genetically engineered immune privileged Sertoli cells  

PubMed Central

Sertoli cells are immune privileged cells, important for controlling the immune response to male germ cells as well as maintaining the tolerogenic environment in the testis. Additionally, ectopic Sertoli cells have been shown to survive and protect co-grafted cells when transplanted across immunological barriers. The survival of ectopic Sertoli cells has led to the idea that they could be used in cell based gene therapy. In this review, we provide a brief overview of testis immune privilege and Sertoli cell transplantation, factors contributing to Sertoli cell immune privilege, the challenges faced by viral vector gene therapy, the use of immune privileged cells in cell based gene therapy and describe several recent studies on the use of genetically engineered Sertoli cells to provide continuous delivery of therapeutic proteins.

Kaur, Gurvinder; Long, Charles R.; Dufour, Jannette M.

2012-01-01

205

Macrophage Cell Line B6MP1O2 Resembles Peritoneal Macrophages in Tumor Cell Recognition and Killing  

Microsoft Academic Search

In this paper we describe the bone marrow-derived macrophage cell line B6MP1O2. We describe growth characteristics, responsiveness to biological response modifiers known to activate macrophages (MPs), and the ability of B6MP1O2-comparabie to that of peritoneal MPs-to kill and discriminate tumor cells. We demonstrate that B6MP1O2 is easily maintained in culture in the presence of 15% L-M cell-conditioned media. We have

Stephen K. Chapes; Elizabeth S. Didier; Wayne A. F. Tompkins

1988-01-01

206

Effects of tamoxifen on estrogen receptor-? level in immune cells and humoral specific response after immunization of C3H/He male mice with syngeneic testicular germ cells (TGC).  

PubMed

Estrogens and estrogen receptors (ERs) are potent regulators of the immune response. Disruption of ER? or modulation of its function by selective ligands during experimental autoimmune conditions changes the course of disease by influencing specific humoral and cellular responses. However, it is not known whether fluctuation in the ER? level and the variable accessibility to its ligands in immune cells influence the development of specific immune responses against auto-antigens. This study was designed to evaluate the expression level of ER? in splenic immune cells and the specific humoral immune response in male C3H/He/W mice immunized with syngeneic testicular germ cells (TGC) in the presence of tamoxifen. Levels of ER? protein in immune cell subpopulations of immunized mice (assessed by flow cytometry) increased in MHCII(+)CD86(+), MHCII(+)CD86(- ), F4/80(+)MHCII(+), immature macrophages (F4/80(+)/MHCII(- )), and CD3(+)CD4(+) T cells. Addition of tamoxifen decreased the level of ER? in MHCII(+)CD86(+), MHCII(+)CD86(- ), F4/80(+)MHCII(+), immature macrophages (F4/80(+)/MHCII(- )), and the CD19(+)CD3(- ) cell subpopulation of immunized mice. Therefore, immunization with syngeneic antigen and tamoxifen treatment evoked cell-type specific changes in the level of ER?. Irrespective of tamoxifen treatment the humoral response in immunized animals toward TGCs was similar, suggesting that modulation of the level of ER? in immune cells is not directly related to specific auto-antibody production. PMID:21329476

Maj, Tomasz; Swita?a-Jelen, Kinga; Miazek, Arkadiusz; Szafarowicz-Basta, Beata; Kiczak, Liliana; Slawek, Anna; Chelmonska-Soyta, Anna

2011-02-18

207

CD40/CD40 ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages.  

PubMed

We have previously shown that T cell receptor-activated mouse T helper (Th)1 clones induce the production of interleukin (IL)-12 by splenic antigen-presenting cells (APC). Here, we show that the expression of CD40L by activated T cells is critical for T cell-dependent IL-12 production by mouse macrophages. IL-12 was produced in cultures containing alloreactive Th1 clones stimulated with allogeneic peritoneal macrophages, or in cultures of splenocytes stimulated with anti-CD3. Anti-CD40L monoclonal antibodies (mAb) inhibited the production of IL-12, but not IL-2, in these cultures by approximately 90% and had dramatic inhibitory effects on antigen-dependent proliferation of Th1 clones. In addition, both activated T cells and a Th1 clone derived from CD40L knockout mice failed to induce IL-12 production from splenic APC or peritoneal macrophages. Finally, macrophages cultured in the absence of T cells produced IL-12 upon stimulation with soluble recombinant CD40L in combination with either supernatants from activated Th1 clones or with interferon-gamma and granulocyte/macrophage colony-stimulating factor. Thus, both CD40L-dependent and cytokine-mediated signals from activated T cells are required to induce the production of IL-12 by macrophages. A blockade at the level of IL-12 production may explain, at least in part, the dramatic ability of anti-CD40L mAb to inhibit disease in animal models that are dependent upon the generation of a cell-mediated immune response. Moreover, a defect in T cell-dependent induction of IL-12 may contribute to the immune status of humans that lack functional CD40L. PMID:8617306

Kennedy, M K; Picha, K S; Fanslow, W C; Grabstein, K H; Alderson, M R; Clifford, K N; Chin, W A; Mohler, K M

1996-02-01

208

Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages  

PubMed Central

During carcinogenesis, tumors induce dysfunctional development of hematopoietic cells. Myeloid lineage cells, in the form of myeloid derived suppressor cells (MDSCs) and alternatively polarized M2 macrophages, influence almost all types of cancers by regulating diverse facets of immunosuppression, angiogenesis, cell proliferation, growth and metastasis. One-third of Americans are obese, and accumulating evidence suggests that obesity is a risk factor for various cancers. However, the relationship between these immune players and obesity are not well-described. In this review, we evaluate potential mechanisms through which different aspects of obesity, namely insulin resistance, increased estrogen, adiposity and low grade chronic inflammation from adipose tissue macrophages, may coalesce to promote MDSC induction and M2 macrophage polarization, thereby facilitating cancer development. Detailed understanding of the interplay between obesity and myeloid mediated immunosuppression may provide novel avenues for therapeutic targeting, with the goal to reduce the challenge obesity presents towards gains made in cancer outcomes.

Okwan-Duodu, Derick; Umpierrez, Guillermo E; Brawley, Otis W; Diaz, Roberto

2013-01-01

209

Dietary fat influences Ia antigen expression and immune cell populations in the murine peritoneum and spleen.  

PubMed

Peritoneal cells (PEC) and splenocytes were obtained from Listeria monocytogene (LM)-infected or noninfected mice fed a 20% fat diet rich in either (n-3) polyunsaturated fatty acids [(n-3) PUFA diet], linoleate [(n-6) PUFA diet], oleate (MONO diet), or saturated fatty acids (SAT diet) for 6 wk and were assessed for T cells, B cells, macrophages and Ia expression by flow cytometric analysis. In the peritoneum of noninfected mice, dietary fat did not affect total cell yield or the percentage of B cells, macrophages or Ia+ cells, but the (n-3) PUFA-fed group had a greater percentage of T cells than did the other groups. Among the LM-infected mice, the (n-3) PUFA-fed group generally had the highest percentage of B cells and the lowest percentages of T cells, macrophages and Ia+ cells in the peritoneum. Listeria monocytogene infection elevated peritoneal T cell numbers in all mice except the (n-3) PUFA-fed group. The density of Ia molecules on PEC was 40% lower in mice fed the (n-3) PUFA diet. In the spleen, dietary fat also influenced the immune cell populations and Ia+ cells. Two-color staining of spleen cells revealed that Ia+ splenocytes were predominately B cells. These data demonstrate that dietary fats influence Ia expression and immune cell populations and that the effects observed in one immune tissue or cell type may not be readily extrapolated to others. PMID:1316956

Huang, S C; Misfeldt, M L; Fritsche, K L

1992-06-01

210

Cell adhesion molecules in invertebrate immunity  

Microsoft Academic Search

Cell adhesion is essential in immunity in invertebrates, e.g., in the cellular immune responses of encapsulation and nodule formation. Here cell adhesion molecules shown or suggested to be involved in invertebrate immunity are reviewed.Blood cells of the crayfish, Pacifastacus leniusculus, can release a cell-adhesive and opsonic peroxidase, peroxinectin. A site containing the motif, KGD, appears to be adhesive by binding

Mats W Johansson

1999-01-01

211

Complement expression in retinal pigment epithelial cells is modulated by activated macrophages.  

PubMed

Complement activation is involved in a variety of retinal diseases. We have shown previously that a number of complement components and regulators can be produced locally in the eye, and that retinal pigment epithelial (RPE) cells are the major source of complement expression at the retina-choroidal interface. The expression of complement components by RPE cells is regulated by inflammatory cytokines. Under aging or inflammatory conditions, microglia and macrophages accumulate in the subretinal space, where they are in close contact with RPE cells. In this study, we investigated the effect of activated macrophages on complement expression by RPE cells. Mouse RPE cells were treated with the supernatants from un-activated bone marrow-derived macrophages (BM-DMs), the classically activated BM-DMs (M1) and different types of the alternatively activated BM-DMs (M2a by IL-4, M2b by immune complex and lipopolysaccharide (LPS), M2c by IL-10). The expression of inflammatory cytokines and complement genes by RPE cells were determined by real-time RT-PCR. The protein expression of CFB, C3, C1INH, and C1r was examined by Western blot. Our results show that un-stimulated RPE cells express a variety of complement-related genes, and that the expression levels of complement regulators, including C1r, factor H (CFH), DAF1, CD59, C1INH, Crry, and C4BP genes are significantly higher than those of complement component genes (C2, C4, CFB, C3, and C5). Macrophage supernatants increased inflammatory cytokine (IL-1?, IL-6, iNOS), chemokine (CCL2) and complement expression in RPE cells. The supernatants from M0, M2a and M2c macrophages mildly up-regulated (2-3.5-fold) CFB, CFH and C3 gene expression in RPE cells, whereas the supernatants from M1 and M2b macrophages massively increased (10-30-fold) CFB and C3 gene expression in RPE cells. The expression of other genes, including C1r, C2, C4, CFH, Masp1, C1INH, and C4BP in RPE cells was also increased by the supernatants of M1 and M2b macrophages; however, the increment levels were significantly lower than CFB and C3 genes. M1 and M2b macrophage supernatants enhanced CFB (Bb fragment) protein expression and C3 secretion by RPE cells. M1 macrophages may affect complement expression in RPE cells through the STAT1 pathway. Our results suggest that under inflammatory conditions, activated macrophages could promote the alternative pathway of complement activation in the retina via induction of RPE cell CFB and C3 expression. PMID:23644095

Luo, Chang; Zhao, Jiawu; Madden, Angelina; Chen, Mei; Xu, Heping

2013-05-01

212

Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?  

PubMed Central

Summary Despite the discovery of the tuberculosis (TB) bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis (MTb). Understanding the genetic and immunologic factors that influence human susceptibility could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease. Although a series of studies over the past 50 years suggests that host genetics influences resistance to TB, a comprehensive understanding of which genes and variants are associated with susceptibility is only partially understood. In this article, we review recent advances in our understanding of human variation of the immune system and its effects on macrophage function and influence on MTb susceptibility. We emphasize recent discoveries in human genetic studies and correlate these findings with efforts to understand how these variants alter the molecular and cellular functions that regulate the macrophage response to MTb.

Berrington, William R.; Hawn, Thomas R.

2010-01-01

213

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.

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

2011-01-01

214

Stimulation of neoplastic mouse lung cell proliferation by alveolar macrophage-derived, insulin-like growth factor-1 can be blocked by inhibiting MEK and PI3K activation  

Microsoft Academic Search

Background  Worldwide, lung cancer kills more people than breast, colon and prostate cancer combined. Alterations in macrophage number\\u000a and function during lung tumorigenesis suggest that these immune effector cells stimulate lung cancer growth. Evidence from\\u000a cancer models in other tissues suggests that cancer cells actively recruit growth factor-producing macrophages through a reciprocal\\u000a signaling pathway. While the levels of lung macrophages increase

Jason M Fritz; Lori D Dwyer-Nield; Alvin M Malkinson

2011-01-01

215

Safrole suppresses murine myelomonocytic leukemia WEHI-3 cells in vivo, and stimulates macrophage phagocytosis and natural killer cell cytotoxicity in leukemic mice.  

PubMed

Many anticancer drugs are obtained from phytochemicals and natural products. However, some phytochemicals have mutagenic effects. Safrole, a component of Piper betle inflorescence, has been reported to be a carcinogen. We have previously reported that safrole induced apoptosis in human oral cancer cells in vitro and inhibited the human oral tumor xenograft growth in vivo. Until now, there is no information addressing if safrole promotes immune responses in vivo. To evaluate whether safrole modulated immune function, BALB/c mice were intraperitoneally injected with murine myelomonocytic WEHI-3 leukemia cells to establish leukemia and then were treated with or without safrole at 4 and 16 mg/kg. Animals were sacrificed after 2 weeks post-treatment with safrole for examining the immune cell populations, phagocytosis of macrophages and the natural killer (NK) cells' cytotoxicity. Results indicated that safrole increased the body weight, and decreased the weights of spleen and liver in leukemic mice. Furthermore, safrole promoted the activities of macrophages phagocytosis and NK cells' cytotoxicity in leukemic mice when compared with untreated leukemic mice. After determining the cell marker population, we found that safrole promoted the levels of CD3 (T cells), CD19 (B cells) and Mac-3 (macrophages), but it did not affect CD11b (monocytes) in leukemic mice. In conclusion, safrole altered the immune modulation and inhibited the leukemia WEHI-3 cells in vivo. © 2011 Wiley Periodicals, Inc. Environ Toxicol 28:601-608, 2013. PMID:24150866

Yu, Fu-Shun; Yang, Jai-Sing; Yu, Chun-Shu; Chiang, Jo-Hua; Lu, Chi-Cheng; Chung, Hsiung-Kwang; Yu, Chien-Chih; Wu, Chih-Chung; Ho, Heng-Chien; Chung, Jing-Gung

2011-08-24

216

CD4+ Valpha14 NKT cells play a crucial role in an early stage of protective immunity against infection with Leishmania major  

Microsoft Academic Search

The roles of ?? T, NK and NKT cells in an early stage of protective immunity against infection with Leishmania major were investigated. Further, the contribution of these innate cells to the expression of 65 kDa heat shock protein (HSP65) in host macrophages was examined, since we found previously that this expression prevents apoptotic death of infected macrophages and is

Hiroyuki Ishikawa; Hajime Hisaeda; Masaru Taniguchi; Toshinori Nakayama; Tohru Sakai; Yoichi Maekawa; Yoko Nakano; Manxin Zhang; Tianqian Zhang; Masaaki Nishitani; Miwa Takashima; Kunisuke Himeno

2000-01-01

217

Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice  

PubMed Central

Summary Repeated social defeat (RSD) activates neuroendocrine pathways that have a significant influence on immunity and behavior. Previous studies from our lab indicate that social defeat enhances the inflammatory capacity of CD11b+ cells in the brain and promotes anxiety-like behavior in an interleukin (IL)-1 and ?-adrenergic receptor-dependent manner. The purpose of this study was to determine the degree to which mice subjected to RSD were more responsive to a secondary immune challenge. Therefore, RSD or control (HCC) mice were injected with saline or lipopolysaccharide (LPS) and activation of brain CD11b+ cells and behavioral responses were determined. Peripheral LPS (0.5 mg/kg) injection caused an extended sickness response with exaggerated weight loss and prolonged social withdrawal in socially defeated mice. LPS injection also amplified mRNA expression of IL-1?, tumor necrosis factor (TNF)-?, inducible nitric oxide synthase (iNOS), and CD14 in enriched CD11b+ cells isolated from socially defeated mice. In addition, IL-1? mRNA levels in enriched CD11b+ cells remained elevated in socially defeated mice 24 h and 72 h after LPS. Moreover, microglia and CNS macrophages isolated from socially defeated mice had the highest CD14 expression after LPS injection. Both social defeat and LPS injection increased the percentage of CD11b+/CD45high macrophages in the brain and the number of inflammatory macrophages (CD11b+/CD45high/CCR2+) was highest in RSD-LPS mice. Anxiety-like behavior was increased by social defeat, but was not exacerbated by the LPS challenge. Nonetheless, reduced locomotor activity and increased social withdrawal were still present in socially defeated mice 72 h after LPS. Last, LPS-induced microglia activation was most evident in the hippocampus of socially defeated mice. Taken together, these findings demonstrate that repeated social defeat enhanced the neuroinflammatory response and caused prolonged sickness following innate immune challenge.

Wohleb, Eric S.; Fenn, Ashley M.; Pacenta, Ann M.; Powell, Nicole D.; Sheridan, John F.; Godbout, Jonathan P.

2012-01-01

218

Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice.  

PubMed

Repeated social defeat (RSD) activates neuroendocrine pathways that have a significant influence on immunity and behavior. Previous studies from our lab indicate that RSD enhances the inflammatory capacity of CD11b? cells in the brain and promotes anxiety-like behavior in an interleukin (IL)-1 and ?-adrenergic receptor-dependent manner. The purpose of this study was to determine the degree to which mice subjected to RSD were more responsive to a secondary immune challenge. Therefore, RSD or control (HCC) mice were injected with saline or lipopolysaccharide (LPS) and activation of brain CD11b? cells and behavioral responses were determined. Peripheral LPS (0.5 mg/kg) injection caused an extended sickness response with exaggerated weight loss and prolonged social withdrawal in socially defeated mice. LPS injection also amplified mRNA expression of IL-1?, tumor necrosis factor (TNF)-?, inducible nitric oxide synthase (iNOS), and CD14 in enriched CD11b? cells isolated from socially defeated mice. In addition, IL-1? mRNA levels in enriched CD11b? cells remained elevated in socially defeated mice 24 h and 72 h after LPS. Moreover, microglia and CNS macrophages isolated from socially defeated mice had the highest CD14 expression after LPS injection. Both social defeat and LPS injection increased the percentage of CD11b?/CD45(high) macrophages in the brain and the number of inflammatory macrophages (CD11b?/CD45(high)/CCR2?) was highest in RSD-LPS mice. Anxiety-like behavior was increased by social defeat, but was not exacerbated by the LPS challenge. Nonetheless, reduced locomotor activity and increased social withdrawal were still present in socially defeated mice 72 h after LPS. Last, LPS-induced microglia activation was most evident in the hippocampus of socially defeated mice. Taken together, these findings demonstrate that repeated social defeat enhanced the neuroinflammatory response and caused prolonged sickness following innate immune challenge. PMID:22386198

Wohleb, Eric S; Fenn, Ashley M; Pacenta, Ann M; Powell, Nicole D; Sheridan, John F; Godbout, Jonathan P

2012-03-02

219

``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

220

Augmenting T Helper Cell Immunity in Cancer  

Microsoft Academic Search

Cancer specific immunity elicited with vaccines has traditionally focused on the activation of the CD8 cytolytic T lymphocyte (CTL) often involving direct stimulation of immunity using HLA-class I binding peptide epitopes. Recently it has become clear that activation of the CTL immune effector arm alone is insufficient to mediate an anticancer response. A major problem is that CD8 T cells

K. L. Knutson; M. L. Disis

2005-01-01

221

Effect of macrophage migration inhibition factor on the content of stromal precursor cells in mouse bone marrow and efficiency of bone marrow precursor cell cloning in vitro.  

PubMed

The content of stromal precursor cells in the bone marrow of mice decreased 2-5.7 times 24 h after injection of macrophage migration inhibition factor in doses of 0.1-50 ng/kg, this reduction depending on the dose of inhibition factor. The content of precursor cells in the bone marrow of mice increased 2-fold 24 h after injection of S. typhimurium bacterial mass. One day after injection of S. typhimurium bacterial mass, the count of precursor cells in mouse spleen was 7-fold higher than 24 h after injection of macrophage migration inhibition factor. The efficiency of cloning of mouse bone marrow stromal precursor cells in vitro was suppressed 1.7-2.8 times in the presence of macrophage migration inhibition factor in doses of 0.1 to 50 ng/ml culture medium. The effect of cloning inhibition was preserved, if macrophage migration inhibition factor was added to the culture medium after 2 days of bone marrow cell culturing. In general, macrophage migration inhibition factor inhibits stromal precursor cells in vivo and in vitro. The data also indicate that macrophage migration inhibition factor is not responsible for rapid and sharp increase in the count of stromal precursor cells after immunization of animals. PMID:19513377

Gorskaya, U F; Tretyakov, O U; Suslov, A P; Nesterenko, V G

2008-12-01

222

p47phox Directs Murine Macrophage Cell Fate Decisions  

PubMed Central

Macrophage differentiation and function are pivotal for cell survival from infection and involve the processing of microenvironmental signals that determine macrophage cell fate decisions to establish appropriate inflammatory balance. NADPH oxidase 2 (Nox2)–deficient chronic granulomatous disease (CGD) mice that lack the gp91phox (gp91phox?/?) catalytic subunit show high mortality rates compared with wild-type mice when challenged by infection with Listeria monocytogenes (Lm), whereas p47phox-deficient (p47phox?/?) CGD mice show survival rates that are similar to those of wild-type mice. We demonstrate that such survival results from a skewed macrophage differentiation program in p47phox?/? mice that favors the production of higher levels of alternatively activated macrophages (AAMacs) compared with levels of either wild-type or gp91phox?/? mice. Furthermore, the adoptive transfer of AAMacs from p47phox?/? mice can rescue gp91phox?/? mice during primary Lm infection. Key features of the protective function provided by p47phox?/? AAMacs against Lm infection are enhanced production of IL-1? and killing of Lm. Molecular analysis of this process indicates that p47phox?/? macrophages are hyperresponsive to IL-4 and show higher Stat6 phosphorylation levels and signaling coupled to downstream activation of AAMac transcripts in response to IL-4 stimulation. Notably, restoring p47phox protein expression levels reverts the p47phox-dependent AAMac phenotype. Our results indicate that p47phox is a previously unrecognized regulator for IL-4 signaling pathways that are important for macrophage cell fate choice.

Yi, Liang; Liu, Qi; Orandle, Marlene S.; Sadiq-Ali, Sara; Koontz, Sherry M.; Choi, Uimook; Torres-Velez, Fernando J.; Jackson, Sharon H.

2012-01-01

223

Differential impact of L-arginine deprivation on the activation and effector functions of T cells and macrophages  

Microsoft Academic Search

The metabolism of the amino acid L- arginine is emerging as a crucial mechanism for the regulation of immune responses. Here, we charac- terized the impact of L-arginine deprivation on T cell and macrophage (M) effector functions: We show that whereas L-arginine is required uncondi- tionally for T cell activation, M can up-regulate activation markers and produce cytokines and che-

B.-S. Choi; I. Clara Martinez-Falero; C. Corset; M. Munder; M. Modolell; I. Muller; P. Kropf

2009-01-01

224

Tissue-resident macrophages.  

PubMed

Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo. PMID:24048120

Davies, Luke C; Jenkins, Stephen J; Allen, Judith E; Taylor, Philip R

2013-09-18

225

Serratia marcescens Induces Apoptotic Cell Death in Host Immune Cells via a Lipopolysaccharide- and Flagella-dependent Mechanism*  

PubMed Central

Injection of Serratia marcescens into the blood (hemolymph) of the silkworm, Bombyx mori, induced the activation of c-Jun NH2-terminal kinase (JNK), followed by caspase activation and apoptosis of blood cells (hemocytes). This process impaired the innate immune response in which pathogen cell wall components, such as glucan, stimulate hemocytes, leading to the activation of insect cytokine paralytic peptide. S. marcescens induced apoptotic cell death of silkworm hemocytes and mouse peritoneal macrophages in vitro. We searched for S. marcescens transposon mutants with attenuated ability to induce apoptosis of silkworm hemocytes. Among the genes identified, disruption mutants of wecA (a gene involved in lipopolysaccharide O-antigen synthesis), and flhD and fliR (essential genes in flagella synthesis) showed reduced motility and impaired induction of mouse macrophage cell death. These findings suggest that S. marcescens induces apoptosis of host immune cells via lipopolysaccharide- and flagella-dependent motility, leading to the suppression of host innate immunity.

Ishii, Kenichi; Adachi, Tatsuo; Imamura, Katsutoshi; Takano, Shinya; Usui, Kimihito; Suzuki, Kazushi; Hamamoto, Hiroshi; Watanabe, Takeshi; Sekimizu, Kazuhisa

2012-01-01

226

A Brucella virulence factor targets macrophages to trigger B-cell proliferation.  

PubMed

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

2013-05-29

227

Gene expression reprogramming protects macrophage from septic-induced cell death.  

PubMed

Sepsis induces a systemic inflammatory response leading to tissue damage and cell death. LPS tolerance affects inflammatory response. To comprehend potential new mechanisms of immune regulation in endotoxemia, we examined macrophage mRNA expression by macroarray affected by LPS tolerance. LPS tolerance was induced with subcutaneous administration of 1 mg/kg/day of LPS over 5 days. Macrophages were isolated from the spleen and the expression of 1200 genes was quantitatively analyzed by the macroarray technique. The tolerant group displayed relevant changes in the expression of 84 mRNA when compared to naïve mice. A functional group of genes related to cell death regulation was identified. PARP-1, caspase 3, FASL and TRAIL genes were confirmed by RT-PCR to present lower expression in tolerant mice. In addition, reduced expression of the pro-inflammatory genes TNF-? and IFN-? in the tolerant group was demonstrated. Following this, animals were challenged with polymicrobial sepsis. Flow cytometry analysis showed reduced necrosis and apoptosis in macrophages from the tolerant group compared to the naïve group. Finally, a survival study showed a significant reduction in mortality in the tolerant group. Thus, in the current study we provide evidence for the selective reprogramming of the gene expression of cell death pathways during LPS tolerance and link these changes to protection from cell death and enhanced survival rates. PMID:20728938

Melo, Edielle Sant'Anna; Barbeiro, Denise F; Gorjão, Renata; Rios, Ester Correia Sarmento; Vasconcelos, Dewton; Velasco, Irineu T; Szabo, Csaba; Curi, Rui; de Lima-Salgado, Thais Martins; Soriano, Francisco Garcia

2010-08-21

228

Revised Recommendations for Red Blood Cell Immunization ...  

Center for Biologics Evaluation and Research (CBER)

Text Version... Source Plasma Donors. To: All Licensed Establishments Performing Red Blood Cell Immunizations Introduction On August ... More results from www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation

229

Immunological aspects of acute ureteral obstruction: Immune cell infiltrate in the kidney  

Microsoft Academic Search

Immunological aspects of acute ureteral obstruction: Immune cell infiltrate in the kidney. Kidneys from rats subjected to bilateral ureteral obstruction (BUO), unilateral ureteral obstruction (UUO) and UUO with subsequent release were analyzed for leukocyte infiltration. A time-dependent influx of leukocytes, predominantly macrophages and suppressor T lymphocytes, occurred in both the cortex and medulla following obstruction, and disappeared with release of

George F Schreiner; Kevin P G Harris; Mabel L Purkerson; Saulo Klahr

1988-01-01

230

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.

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

2009-01-01

231

Influence of Costimulatory Molecules on Immune Response to Leishmania major by Human Cells In Vitro  

Microsoft Academic Search

The importance of CD40, CD80, and CD86 costimulatory molecules in anti-Leishmania immune responses has been established in murine models. A role for these costimulatory molecules in human anti-Leishmania immune responses was investigated in this study. Autologous macrophages and peripheral blood leukocytes (PBL) were prepared from peripheral blood mononuclear cells of Leishmania-naive donors and cultured with or without Leishmania major in

CLAUDIA I. BRODSKYN; GREGORY K. DEKREY; RICHARD G. TITUS

2001-01-01

232

Impact of Host Membrane Pore Formation by the Yersinia pseudotuberculosis Type III Secretion System on the Macrophage Innate Immune Response  

PubMed Central

Type III secretion systems (T3SSs) are used by Gram-negative pathogens to form pores in host membranes and deliver virulence-associated effector proteins inside host cells. In pathogenic Yersinia, the T3SS pore-forming proteins are YopB and YopD. Mammalian cells recognize the Yersinia T3SS, leading to a host response that includes secretion of the inflammatory cytokine interleukin-1? (IL-1?), Toll-like receptor (TLR)-independent expression of the stress-associated transcription factor Egr1 and the inflammatory cytokine tumor necrosis factor alpha (TNF-?), and host cell death. The known Yersinia T3SS effector proteins are dispensable for eliciting these responses, but YopB is essential. Three models describe how the Yersinia T3SS might trigger inflammation: (i) mammalian cells sense YopBD-mediated pore formation, (ii) innate immune stimuli gain access to the host cytoplasm through the YopBD pore, and/or (iii) the YopB-YopD translocon itself or its membrane insertion is proinflammatory. To test these models, we constructed a Yersinia pseudotuberculosis mutant expressing YopD devoid of its predicted transmembrane domain (YopD?TM) and lacking the T3SS cargo proteins YopHEMOJTN. This mutant formed pores in macrophages, but it could not mediate translocation of effector proteins inside host cells. Importantly, this mutant did not elicit rapid host cell death, IL-1? secretion, or TLR-independent Egr1 and TNF-? expression. These data suggest that YopBD-mediated translocation of unknown T3SS cargo leads to activation of host pathways influencing inflammation, cell death, and response to stress. As the YopD?TM Y. pseudotuberculosis mutant formed somewhat smaller pores with delayed kinetics, an alternative model is that the wild-type YopB-YopD translocon is specifically sensed by host cells.

Kwuan, Laura; Adams, Walter

2013-01-01

233

Impact of host membrane pore formation by the Yersinia pseudotuberculosis type III secretion system on the macrophage innate immune response.  

PubMed

Type III secretion systems (T3SSs) are used by Gram-negative pathogens to form pores in host membranes and deliver virulence-associated effector proteins inside host cells. In pathogenic Yersinia, the T3SS pore-forming proteins are YopB and YopD. Mammalian cells recognize the Yersinia T3SS, leading to a host response that includes secretion of the inflammatory cytokine interleukin-1? (IL-1?), Toll-like receptor (TLR)-independent expression of the stress-associated transcription factor Egr1 and the inflammatory cytokine tumor necrosis factor alpha (TNF-?), and host cell death. The known Yersinia T3SS effector proteins are dispensable for eliciting these responses, but YopB is essential. Three models describe how the Yersinia T3SS might trigger inflammation: (i) mammalian cells sense YopBD-mediated pore formation, (ii) innate immune stimuli gain access to the host cytoplasm through the YopBD pore, and/or (iii) the YopB-YopD translocon itself or its membrane insertion is proinflammatory. To test these models, we constructed a Yersinia pseudotuberculosis mutant expressing YopD devoid of its predicted transmembrane domain (YopD(?TM)) and lacking the T3SS cargo proteins YopHEMOJTN. This mutant formed pores in macrophages, but it could not mediate translocation of effector proteins inside host cells. Importantly, this mutant did not elicit rapid host cell death, IL-1? secretion, or TLR-independent Egr1 and TNF-? expression. These data suggest that YopBD-mediated translocation of unknown T3SS cargo leads to activation of host pathways influencing inflammation, cell death, and response to stress. As the YopD(?TM) Y. pseudotuberculosis mutant formed somewhat smaller pores with delayed kinetics, an alternative model is that the wild-type YopB-YopD translocon is specifically sensed by host cells. PMID:23297383

Kwuan, Laura; Adams, Walter; Auerbuch, Victoria

2013-01-07

234

Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells  

PubMed Central

Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance.

Dalal, Samay; Horstmann, Sarah A.; Richens, Tiffany R.; Tanaka, Takeshi; Doe, Jenna M.; Boe, Darren M.; Voelkel, Norbert F.; Taraseviciene-Stewart, Laimute; Janssen, William J.; Lee, Chun G.; Elias, Jack A.; Bratton, Donna; Tuder, Rubin M.; Henson, Peter M.; Vandivier, R. William

2012-01-01

235

Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells.  

PubMed

Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance. PMID:22307908

Kearns, Mark T; Dalal, Samay; Horstmann, Sarah A; Richens, Tiffany R; Tanaka, Takeshi; Doe, Jenna M; Boe, Darren M; Voelkel, Norbert F; Taraseviciene-Stewart, Laimute; Janssen, William J; Lee, Chun G; Elias, Jack A; Bratton, Donna; Tuder, Rubin M; Henson, Peter M; Vandivier, R William

2012-02-03

236

Survival Strategy of Obligately Intracellular Ehrlichia chaffeensis: Novel Modulation of Immune Response and Host Cell Cycles  

PubMed Central

Ehrlichia chaffeensis is an obligatory intracellular bacterium which resides in an early endosome in monocytes. E. chaffeensis infection in a human monocyte cell line (THP1) significantly altered the transcriptional levels of 4.5% of host genes, including those coding for apoptosis inhibitors, proteins regulating cell differentiation, signal transduction, proinflammatory cytokines, biosynthetic and metabolic proteins, and membrane trafficking proteins. The transcriptional profile of the host cell revealed key themes in the pathogenesis of Ehrlichia. First, E. chaffeensis avoided stimulation of or repressed the transcription of cytokines involved in the early innate immune response and cell-mediated immune response to intracellular microbes, such as the interleukin-12 (IL-12), IL-15, and IL-18 genes, which might make Ehrlichia a stealth organism for the macrophage. Second, E. chaffeensis up-regulated NF-?B and apoptosis inhibitors and differentially regulated cell cyclins and CDK expression, which may enhance host cell survival. Third, E. chaffeensis also inhibited the gene transcription of RAB5A, SNAP23, and STX16, which are involved in membrane trafficking. By comparing the transcriptional response of macrophages infected with other bacteria and that of macrophages infected with E. chaffeensis, we have identified few genes that are commonly induced and no commonly repressed genes. These results illustrate the stereotyped macrophage response to other pathogens, in contrast with the novel host response to obligate intracellular Ehrlichia, whose survival depends entirely on a long evolutionary process of outmaneuvering macrophages.

Zhang, Jian-zhi; Sinha, Mala; Luxon, Bruce A.; Yu, Xue-jie

2004-01-01

237

Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells  

PubMed Central

Summary Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential niche component that supports malignant plasma cells. We investigated the proliferation of MM tumour cell lines when cultured alone or together with MSCs, macrophages, or a combination of MSCs and macrophages, using the carboxyfluorescein succinimidyl ester assay. Consistently, we observed increased proliferation of MM cell lines in the presence of either MSCs or macrophages compared to cell line-only control. Furthermore, the combined co-culture of MSCs plus macrophages induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, MSCs and macrophages decreased the rate of apoptosis of myeloma cells. Our in vitro studies provide evidence that highlights the role of macrophages as a key component of the BM microenvironment facilitating the growth of malignant plasma cells in MM.

Kim, Jaehyup; Denu, Ryan A; Dollar, Bridget A; Escalante, Leah E; Kuether, Justin P; Callander, Natalie S; Asimakopoulos, Fotis; Hematti, Peiman

2012-01-01

238

Characterization of Tumor Binding by the IC21 Macrophage Cell Line1  

Microsoft Academic Search

The purpose of this study was to determine if the SV40-transformed murine macrophage cell line IC-21 is a suitable model to study the selective high avidity binding of tumor cells by subpopulations of activated macrophages. IC-21 macrophages bound P815, RBL5, and EL-4 murine tumor cells with high avidity, as measured by the inverted centrifugation method. Tumor binding by IC-21 macrophages

Eric K. Crawford; Patricia S. Latham; Eliza M. Shah; Jeffrey D. Hasday

1990-01-01

239

In the Absence of Endogenous Gamma Interferon, Mice Acutely Infected with Neospora caninum Succumb to a Lethal Immune Response Characterized by Inactivation of Peritoneal Macrophages  

PubMed Central

Following infection with Neospora caninum, BALB/c mice were shown to be resistant to an acute infection but developed a latent chronic infection. However, BALB/c background gamma interferon (IFN-?)-deficient mice were sensitive to the acute infection. Since the immune response in IFN-?-deficient mice is scantly known, we examined the function of macrophages, major histocompatibility complex (MHC) class II expression, T-cell responses, and serum cytokine levels in the mice. All IFN-?-deficient mice died within 9 days of infection with N. caninum, whereas those treated with exogenous IFN-? lived longer. Although N. caninum invaded various organs in both types of mice at the early stage of infection, the parasite was not detected in the brains of resistant hosts until 21 days postinfection (dpi). Peritoneal macrophages from IFN-?-deficient mice were activated by exogenous IFN-? associated with inhibition of parasite growth and nitric oxide production as were those from BALB/c mice. IFN-?-deficient mice failed to increase MHC class II expression on macrophages. Moreover, BALB/c mice induced T-cell proliferation while IFN-?-deficient mice did not. However, in vivo treatment with exogenous IFN-? induced up-regulated MHC class II expression in IFN-?-deficient mice. BALB/c mice treated with an antibody to CD4 showed an increase in morbidity and mortality after parasite infection. In serum, significant levels of IFN-? and interleukin-4 (IL-4) were detected in resistant hosts, whereas IL-10 was detected in IFN-?-deficient mice. The levels of IL-12 in IFN-?-deficient mice were higher than those in BALB/c mice at 7 dpi. The present study indicates that early IFN-? production has a crucial role in the activation of peritoneal macrophages for the induction of protective immune responses against N. caninum.

Nishikawa, Yoshifumi; Tragoolpua, Khajornsak; Inoue, Noboru; Makala, Levi; Nagasawa, Hideyuki; Otsuka, Haruki; Mikami, Takeshi

2001-01-01

240

Cell surface receptor FPR2 promotes antitumor host defense by limiting M2 polarization of macrophages.  

PubMed

FPR2 (Fpr2 in mouse) is a G-protein-coupled receptor interacting with bacterial and host-derived chemotactic agonists. Fpr2 supports innate and adaptive immune responses as illustrated by the reduction in severity of allergic airway inflammation in Fpr2-KO mice, due to impaired trafficking of antigen-presenting dendritic cells (DC). The aim of this study is to examine the role of Fpr2 in host antitumor responses. We found that Fpr2-KO mice bearing subcutaneously implanted Lewis lung carcinoma (LLC) cells exhibited significantly shortened survival than normal mice due to more rapidly growing tumors. In contrast, in Fpr2-transgenic mice overexpressing Fpr2, subcutaneously implanted LLC tumors grew more slowly than those in wild-type (WT) littermates. Investigation of tumor tissues revealed an increased number of macrophages associated with tumors grown in Fpr2-KO mice. Macrophages derived from Fpr2-KO mice showed a more potent chemotactic response to LLC-derived supernatant (LLC Sup), which could be neutralized by an anti-CCL2 antibody. The increased chemotaxis of Fpr2-KO mouse macrophages in response to LLC Sup was due to their higher level expression of CCR4, a chemokine receptor that also recognizes the ligand CCL2. Furthermore, macrophages from Fpr2-KO mice acquired an M2 phenotype after stimulation with LLC Sup. These results suggest that Fpr2 plays an important role in host defense against implanted LLC by sustaining macrophages in an M1 phenotype with more potent antitumor activities. PMID:23139214

Liu, Ying; Chen, Keqiang; Wang, Chunyan; Gong, Wanghua; Yoshimura, Teizo; Liu, Mingyong; Wang, Ji Ming

2012-11-08

241

Neutrophils and Macrophages: the Main Partners of Phagocyte Cell Systems  

PubMed Central

Biological cellular systems are groups of cells sharing a set of characteristics, mainly key function and origin. Phagocytes are crucial in the host defense against microbial infection. The previously proposed phagocyte cell systems including the most recent and presently prevailing one, the mononuclear phagocyte system (MPS), grouped mononuclear cells but excluded neutrophils, creating an unacceptable situation. As neutrophils are archetypical phagocytes that must be members of comprehensive phagocyte systems, Silva recently proposed the creation of a myeloid phagocyte system (MYPS) that adds neutrophils to the MPS. The phagocytes grouped in the MYPS include the leukocytes neutrophils, inflammatory monocytes, macrophages, and immature myeloid DCs. Here the justifications behind the inclusion of neutrophils in a phagocyte system is expanded and the MYPS are further characterized as a group of dedicated phagocytic cells that function in an interacting and cooperative way in the host defense against microbial infection. Neutrophils and macrophages are considered the main arms of this system.

Silva, Manuel T.; Correia-Neves, Margarida

2012-01-01

242

Decreased TNF-? synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging  

PubMed Central

Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4+ T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-? secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-? after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging.

Agius, Elaine; Lacy, Katie E.; Vukmanovic-Stejic, Milica; Jagger, Ann L.; Papageorgiou, Anna-Pia; Hall, Sue; Reed, John R.; Curnow, S. John; Fuentes-Duculan, Judilyn; Buckley, Christopher D.; Salmon, Mike; Taams, Leonie S.; Krueger, James; Greenwood, John; Klein, Nigel; Rustin, Malcolm H.A.

2009-01-01

243

[Indirubin inhibits ATP-induced phagocytosis attenuation, ROS production and cell death of macrophages].  

PubMed

This study is to investigate the effects of indirubin on ATP-induced immune responses of macrophages. For this, neutral red dye uptake method was used to test phagocytosis, MTT assay was used for measuring cell death, and reactive oxygen species (ROS) was tested with fluorescent probe DHE. The data showed that extracellular ATP attenuated phagocytosis, induced cell death and increased ROS production, and these effects were restored by pre-treating with indirubin. This result suggested that indirubin blockade the effects of ATP on macrophages, because extracellular ATP-induced effects are dependent on P2 receptors, in particular P2X7 receptors. Furthermore, the effects of indirubin on the activation of P2 receptors were tested, in particular P2X7 receptors. The data showed that indirubin significantly decreased ATP-induced, P2 receptors mediated intracellular Ca2+ concentration ([Ca2+]i) rise and inhibited P2X7 receptor-based ethidium bromide (EB) dye uptake. These results suggested the inhibitory effects of indirubin on the activation of P2X7 receptors, which may underlying the effects on ATP induced ROS production, phagocytosis attenuation and cell death of macrophages. PMID:22493804

Man, Yuan; Wang, Yu-Xiang; Zhu, Shu-Yan; Yang, Shuang; Zhao, Dan; Hu, Fen; Li, Jun-Ying

2012-01-01

244

Role of immune cells in animal models for inherited neuropathies: facts and visions*  

PubMed Central

Mice heterozygously deficient in the peripheral myelin adhesion molecule P0 (P0+/? mice) are models for some forms of Charcot–Marie–Tooth (CMT) neuropathies. In addition to the characteristic hallmarks of demyelination, elevated numbers of CD8-positive T-lymphocytes and F4/80-positive macrophages are striking features in the nerves of these mice. These immune cells increase in number with age and progress of demyelination, suggesting that they might be functionally related to myelin damage. In order to investigate the pathogenetic role of lymphocytes, the myelin mutants were cross-bred with recombination activating gene 1 (RAG-1)-deficient mice, which lack mature T-and B-lymphocytes. The immunodeficient myelin mutants showed a less severe myelin degeneration. The beneficial effect of lymphocyte-deficiency was reversible, since demyelination worsened in immunodeficient myelin-mutants when reconstituted with bone marrow from wild-type mice. Ultrastructural analysis revealed macrophages in close apposition to myelin and demyelinated axons. We therefore cross-bred the P0+/? mice with spontaneous osteopetrotic (op) mutants deficient in the macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the corresponding double mutants the numbers of macrophages were not elevated in the peripheral nerves, and the demyelinating phenotype was less severe than in the genuine P0+/? mice, demonstrating that macrophages are also functionally involved in the pathogenesis of genetically mediated demyelination. We also examined other models for inherited neuropathies for a possible involvement of immune cells. We chose mice deficient in the gap junction component connexin 32, a model for the X-linked form of CMT. Similar to P0-deficient mice, T-lymphocytes and macrophages were elevated and macrophages showed a close apposition to degenerating myelin. We conclude that the involvement of T-lymphocytes and macrophages is a common pathogenetic feature in various forms of slowly progressive inherited neuropathies.

Maurer, Mathias; Kobsar, Igor; Berghoff, Martin; Schmid, Christoph D; Carenini, Stefano; Martini, Rudolf

2002-01-01

245

Inhibition of T Cell Proliferation by Macrophage Tryptophan Catabolism  

PubMed Central

We have recently shown that expression of the enzyme indoleamine 2,3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell–derived signals IFN-? and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.

Munn, David H.; Shafizadeh, Ebrahim; Attwood, John T.; Bondarev, Igor; Pashine, Achal; Mellor, Andrew L.

1999-01-01

246

Glutamine and the immune system  

Microsoft Academic Search

Summary Glutamine is utilised at a high rate by cells of the immune system in culture and is required to support optimal lymphocyte proliferation and production of cytokines by lymphocytes and macrophages. Macrophage-mediated phagocytosis is influenced by glutamine availability. Hydrolysable glutamine dipeptides can substitute for glutamine to support in vitro lymphocyte and macrophage functions. In man plasma and skeletal muscle

P. C. Calder; P. Yaqoob

1999-01-01

247

Macrophages prevent human red blood cell reconstitution in immunodeficient mice  

PubMed Central

An animal model supporting human erythropoiesis will be highly valuable for assessing the biologic function of human RBCs under physiologic and disease settings, and for evaluating protocols of in vitro RBC differentiation. Herein, we analyzed human RBC reconstitution in NOD/SCID or NOD/SCID/?c?/? mice that were transplanted with human CD34+ fetal liver cells and fetal thymic tissue. Although a large number of human CD45?CD71+ nucleated immature erythroid cells were detected in the bone marrow, human RBCs were undetectable in the blood of these mice. Human RBCs became detectable in blood after macrophage depletion but disappeared again after withdrawal of treatment. Furthermore, treatment with human erythropoietin and IL-3 significantly increased human RBC reconstitution in macrophage-depleted, but not control, humanized mice. Significantly more rapid rejection of human RBCs than CD47-deficient mouse RBCs indicates that mechanisms other than insufficient CD47-SIRP? signaling are involved in human RBC xenorejection in mice. All considered, our data demonstrate that human RBCs are highly susceptible to rejection by macrophages in immunodeficient mice. Thus, strategies for preventing human RBC rejection by macrophages are required for using immunodeficient mice as an in vivo model to study human erythropoiesis and RBC function.

Hu, Zheng; Van Rooijen, Nico

2011-01-01

248

Polyclonal immunoglobulin synthesis induced by a macrophage factor acting via T cells.  

PubMed Central

New Zealand White rabbits were killed 7 days after immunization with 1 mg of alum precipitated, keyhole limpet hemocyanin (KLH) into each hind footpad and 3 days after intraperitoneal injection of thioglycollate. When supernatants from cultures of purified, elicited macrophages were added to Mishell-Dutton cultures of primed popliteal lymphocytes, they induced synthesis of both general immunoglobulins and antibody specific for KLH. The active factor(s), polyclonal lymphocyte activator (PLA), appears to be a glycoprotein with a molecular weight between 150,000 and 200,000 daltons. Absorption with high concentrations of thymocytes but not bone marrow cells removed polyclonal stimulatory activity from peritoneal macrophage supernatants which contained PLA. Purified lymph-node B cells were stimulated by PLA only in the presence of T cells. In addition, supernatants from PLA activated, washed T cells were effective at inducing polyclonal B-cell activation. Thus, PLA appears to act indirectly on B cells by stimulating T cells to produce a soluble factor which induces polyclonal B-cell activation. Images Figure 2

Waldrep, J C; Reese, A C

1981-01-01

249

CD28 ligation increases macrophage suppression of T cell proliferation  

PubMed Central

When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T cell response. Peritoneal macrophages exhibit an immature phenotype (MHC Class IIlo, B7lo) that reduces their efficacy as antigen presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T cell costimulation to recover the peritoneal T cell response. We show that CD28 ligation failed to recover the peritoneal T cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing mAb treatment, this “co-suppression” response was due to CD28 ligation increasing the number of IFN?-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T cell costimulation biology.

Silberman, Daniel; Bucknum, Amanda; Bartlett, Thomas; Composto, Gabriella; Kozlowski, Megan; Walker, Amanda; Werda, Amy; Cua, Jackelyn; Sharpe, Arlene H.; Somerville, John E.; Riggs, James E.

2012-01-01

250

Host microenvironment in breast cancer development: Inflammatory and immune cells in tumour angiogenesis and arteriogenesis  

PubMed Central

Breast cancer progression is associated with and dependent upon robust neovascularization. It is becoming clear that tumour-associated 'normal' cells, such as immune/inflammatory cells, endothelial cells and stromal cells, conspire with cancer cells in promoting this process. In particular, infiltrating immune/inflammatory cells secrete a diverse repertoire of growth factors and proteases that enable them to enhance tumour growth by stimulating angiogenesis and, as we suggest here, by promoting 'tumour arteriogenesis' – enlargement of feeding vessels supplying the expanding tumour capillary bed. Macrophages and their chemoattractants (e.g. macrophage chemoattractant protein-1) are critical for the arteriogenic process in ischaemia, and probably also in breast neoplasia. A better understanding of these various cellular and molecular constituents of breast cancer neovascularization may be useful in designing more effective therapies.

Yu, Joanne L; Rak, Janusz W

2003-01-01

251

CELLS INVOLVED IN THE IMMUNE RESPONSE  

PubMed Central

By appropriate irradiation and cell transfer experiments, a direct correlation was observed between the presence of viable and immunologically active antigen-reactive cells and the capacity of the rabbits to respond following immunization. Rabbits given 800 R total body irradiation were unable to elicit a humoral immune response nor did they possess significant numbers of antigen-reactive cells. The ability to respond with humoral antibody formation did not reappear until antigen-reactive cells could be detected. These results strongly indicate that the presence of competent antigen-reactive cells are necessary for the successful induction of the humoral immune response in the rabbit.

Abdou, Nabih I.; Rose, Bram; Richter, Maxwell

1969-01-01

252

The timing of TNF and IFN-? signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection  

Microsoft Academic Search

During most infections, the population of immune cells known as macrophages are key to taking up and killing bacteria as an integral part of the immune response. However, during infection with Mycobacterium tuberculosis (Mtb), host macrophages serve as the preferred environment for mycobacterial growth. Further, killing of Mtb by macrophages is impaired unless they become activated. Activation is induced by

J. Christian J. Ray; Jian Wang; John Chan; Denise E. Kirschner

2008-01-01

253

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2  

Microsoft Academic Search

Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV rep-

Kazuo Nakamichi; Satoshi Inoue; Tomohiko Takasaki; Kinjiro Morimoto; Ichiro Kurane

2004-01-01

254

Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration.  

PubMed

Tumour-associated macrophages (TAMs) of the M2 phenotype are present in the stroma of many tumours and are frequently associated with the progression of several types of cancer. We investigated the role of M2 macrophages in colon cancer progression and found that human colon cancer tissue had elevated numbers of CD68(+) (macrophage marker) cells and CD206(+) (M2 macrophage marker) cells and increased CD47 expression. To explore potential interplay between colon cancer cells and M2 macrophages, we differentiated the monocyte cell line THP-1 into M1 and M2 macrophages (CD206(high) and Th2 cytokine-secreting cells), respectively. M2 macrophages migrated faster than M1 macrophages towards SW480-conditioned medium. Similarly, M2 macrophage-conditioned medium induced SW480 cell migration and CD47 expression. Factors released by macrophages were involved in this induction. In addition, SW480 cells migrated faster when co-cultured with M2 macrophages. Inhibition of CD47 with blocking antibodies or siRNA significantly reduced the migration of SW480 cells in the presence of M2 macrophages. This effect was further decreased via blocking antibodies against the CD47 ligand signal-regulatory protein ? (SIRP?). Additionally, cancer cells also secreted significant levels of IL-10, thereby promoting M2 macrophage differentiation. These findings indicate that a TAM-enriched tumour microenvironment promotes colon cancer cell migration and metastasis. PMID:23810249

Zhang, Yuan; Sime, Wondossen; Juhas, Maria; Sjölander, Anita

2013-06-26

255

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.

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

256

The transfer of host MHC class I protein protects donor cells from NK cell and macrophage-mediated rejection during hematopoietic stem cell transplantation and engraftment in mice.  

PubMed

Human hematopoietic stem cell engraftment has been studied extensively using xenograft transplant models with immunocompromised mice. It is standard practice to incorporate mouse models, such as the limiting dilution assay, to accurately assess the number of repopulating stem cells in bone marrow or umbilical cord blood collections or to confirm the long-term repopulating ability of cultured hematopoietic stem cells. In a previous study using a standard NOD/SCID mouse model to assess human hematopoietic stem cell engraftment we observed that all human cells had mouse MHC class I protein on their surface, suggesting that this is a mechanism adopted by the cells to evade host immune surveillance. To determine whether this was a xenograft phenomenon we studied host MHC transfer in an intraspecies mouse model and observed similar results. The transfer of MHC class I proteins has implications for antigen presentation and immune modulation. In this report, we used a standard mouse model of bone marrow transplantation to demonstrate that surface protein transfer between cells plays an important role in protecting donor hematopoietic cells from NK cell and macrophage-mediated rejection. The transfer of intact MHC class I antigens from host cells to transplanted donor cells confers a self identity on these otherwise foreign cells. This gives them the ability to evade detection by the host NK cells and macrophages. Once full donor chimerism is established, transplanted cells no longer require host MHC class I protein transfer to survive. Stem Cells 2013;31:2242-2252. PMID:23818226

Chow, Theresa; Whiteley, Jennifer; Li, Mira; Rogers, Ian M

2013-10-01

257

?-1,4-mannobiose stimulates innate immune responses and induces TLR4-dependent activation of mouse macrophages but reduces severity of inflammation during endotoxemia in mice.  

PubMed

?-1,4-Mannobiose (MNB) has been shown to exert prebiotic activity and modulate mucosal gene expression. In this study, the immune-modulating effect of MNB in healthy and endotoxemic mice and its role in Toll-like receptor (TLR) 2/4-mediated macrophage activation were investigated. Mice were supplemented daily with MNB (0, 5, 10, or 25 mg/kg) for 14 d. To examine the effect of MNB during endotoxemia, mice were supplemented with or without MNB (25 mg/kg) for 14 d, followed by challenge with intraperitoneal LPS or saline. MNB induced expression of both T helper (Th) 1- and Th2-type cytokines in the ileum (P < 0.05) and increased fecal IgA production and splenic NK cell activity (P < 0.05) in healthy mice. In endotoxemic mice, MNB reduced the expression of Tnfa, Il-6, iNos (P < 0.05), and Il-10 (P < 0.05), and reduced LPS-induced weight loss but increased Ifng, Il-12p40, Il-5, and Ifna expression (P < 0.05) and NK cell activity relative to positive control (LPS) mice. Treatment of RAW 264.7 macrophages with MNB induced TNF-? and IL-6 secretion (P < 0.05), and this effect was abrogated by inhibiting TLR4, but not TLR2, signaling. Pretreatment of RAW 264.7 cells with MNB induced tolerance to TLR2 and TLR4 agonists, reducing TNF-? production (P < 0.05) upon secondary stimulation with LPS or lipoteichoic acid. These results indicate that MNB can modulate intestinal and systemic immune responses in healthy and endotoxemic mice and prevent LPS-induced immune suppression, as well as directly stimulating innate immune mechanisms in vitro as a TLR4 agonist. PMID:23343679

Kovacs-Nolan, Jennifer; Kanatani, Hiroyuki; Nakamura, Akihiro; Ibuki, Masahisa; Mine, Yoshinori

2013-01-23

258

Nucleotide-binding oligomerization domain 2 (Nod2) is dispensable for the innate immune responses of macrophages against Yersinia enterocolitica.  

PubMed

Nucleotide-binding oligomerization domain 2 (Nod2) is a cytosolic sensor for muramyl dipeptide, a component of bacterial peptidoglycan. In this study, we have examined whether Nod2 mediates the immune response of macrophages against Yersinia enterocolitica. Bone-marrow-derived macrophages (BMDMs) were isolated from WT and Nod2-deficient mice and were infected with various strains of Y. enterocolitica. ELISA showed that the production of IL-6 and TNF-? in BMDMs infected with Y. enterocolitica was not affected by the Nod2 deficiency. iNOS mRNA expression was induced in both WT and Nod2-deficienct BMDMs in response to Y. enterocolitica, beginning 2 h after infection. Nitric oxide (NO) production by Y. enterocolitica did not differ between WT and Nod2-deficient BMDMs. Western blot analysis revealed that Y. enterocolitica induces activation of NF-?B, p38, and ERK MAPK through a Nod2-independent pathway. Neither LDH release by Y. enterocolitica nor the phagocytic activity of the macrophages was altered by Nod2 deficiency. An in vivo experiment showed that bacterial clearance ability and production of IL-6 and KC in serum were comparable in WT and Nod2-deficient mice infected with Y. enterocolitica. These findings suggest that Nod2 may not be critical for initiating the innate immune response of macrophages against Yersinia infection. PMID:22752913

Jeong, Yu-Jin; Kim, Chang-Hwan; Song, Eun-Jung; Kang, Min-Jung; Kim, Jee-Cheon; Oh, Sang-Muk; Lee, Kyung-Bok; Park, Jong-Hwan

2012-06-30

259

The role of macrophage lineage cells in kidney graft rejection and survival.  

PubMed

Large numbers of macrophage lineage cells are present in transplants undergoing ischemia-reperfusion injury and rejection, and their presence correlates with a high probability of rejection. However, the extent to which monocytes and macrophages contribute to kidney graft rejection is poorly understood. The heterogeneity of the monocyte/macrophage lineage cells could be one of the reasons why these cells have been neglected up to now. Circulating monocytes can be divided into various subsets, which are able to give rise to tissue macrophages and dendritic cells. Macrophages are believed to be highly plastic cells that can respond to environmental signals by changing their phenotype and function. Macrophages have established roles in early and late kidney graft inflammation, tissue homeostasis, remodeling, and repair. In kidney transplantation, macrophages are believed to play a role in both damage and repair of the graft, depending on the type of macrophages involved, the environmental drive, and the time after transplantation. The heterogeneity and plasticity of monocytes and macrophages are obstacles to translating the functional relevance of this cell lineage to diagnostic and prognostic clinical parameters and to defining specific, macrophage-related, therapeutic targets. Recent evidence has indicated an immunomodulatory role for the so-called regulatory macrophages in induction of tolerance in kidney transplant recipients. In this article, we summarize current views on monocyte/macrophage immunobiology in kidney transplantation. Key issues for ongoing research are discussed. PMID:22828735

Rowshani, Ajda Tahereh; Vereyken, Elly Johanna Francisca

2012-08-27

260

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. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22972382

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

2012-09-12

261

Mediation of immunity to intracellular infection (Toxoplasma and Besnoitia) within somatic cells.  

PubMed Central

Antigen-treated lymphocytes from immune hamsters specifically protected not only macrophages, but also cultured fibroblasts and kidney cells infected with Toxoplasma gondii or Besnoitia jellisoni. Macrophages were not necessary for the protection of fibroblasts and kidney cells. A mediator that inhibited the intracellular proliferation of these microbes was obtained from immune lymphocytes in contact with specific antigen. Again, macrophages were not necessary for the elaboration of this mediator or its activity in kidney cells or fibroblasts. The mediator was microbe and host specific, had a molecular weight between 4,000 and 5,000, was resistant to heating at 56 degrees C for 30 min, and was sensitive to chymotrypsin, but resistant to ribonuclease and deoxyribonuclease. A single injection of Besnoitia mediator afforded better protection to hamsters infected with Besnoitia than did antibody. Whereas antibody lysed extracellular organisms, the microbe-specific mediators conferred immunity not only on macrophages, but also on other cells of the body, apparently the first such demonstration. Images

Chinchilla, M; Frenkel, J K

1978-01-01

262

T cell functions in granulocyte/macrophage colony-stimulating factor deficient mice  

PubMed Central

Immunological functions were analyzed in mice lacking granulocyte/macrophage colony-stimulating factor (GM-CSF). The response of splenic T cells to allo-antigens, anti-mouse CD3 mAb, interleukin 2 (IL-2), or concanavalin A was comparable in GM-CSF +/+ and GM-CSF ?/? mice. To investigate the responses of CD8+ and CD4+ T cells against exogenous antigens, mice were immunized with ovalbumin peptide or with keyhole limpet hemocyanin (KLH). Cytotoxic CD8+ T cells with specificity for ovalbumin peptide could not be induced in GM-CSF ?/? mice. After immunization with KLH, there was a delay in IgG generation, particularly IgG2a, in GM-CSF ?/? mice. Purified CD4+ T cells from GM-CSF ?/? mice immunized with KLH showed impaired proliferative responses and produced low amounts of interferon-? (IFN-?) and IL-4 when KLH-pulsed B cells or spleen cells were used as antigen presenting cells (APC). When enriched dendritic cells (DC) were used as APC, CD4+ T cells from GM-CSF ?/? mice proliferated as well as those from GM-CSF +/+ mice and produced high amounts of IFN-? and IL-4. To analyze the rescue effect of DC on CD4+ T cells, supernatants from (i) CD4+ T cells cultured with KLH-pulsed DC or (ii) DC cultured with recombinant GM-CSF were transferred to cultures of CD4+ T cells and KLH-pulsed spleen cells from GM-CSF ?/? mice. Supernatants from both DC sources contained a factor or factors that restored proliferative responses and IFN-? production of CD4+ T cells from GM-CSF ?/? mice.

Wada, Hisashi; Noguchi, Yuji; Marino, Michael W.; Dunn, Ashley R.; Old, Lloyd J.

1997-01-01

263

Inflammatory mediator profiling reveals immune properties of chemotactic gradients and macrophage mediator production inhibition during thioglycollate elicited peritoneal inflammation.  

PubMed

Understanding of spatiotemporal profiling of inflammatory mediators and their associations with M? accumulation is crucial to elucidate the complex immune properties. Here, we used murine thioglycollate elicited peritonitis to determine concentrations of 23 inflammatory mediators in peritoneal exudates and plasma before (day 0) and after (days 1 and 3) thioglycollate administration to peritoneal cavities; these mediators included TNF-? , FGF-9, IFN-? , IP-10, RANTES, IL-1? , IL-6, IL-7, IL-10, IL-11, IL-12p70, IL-17A, lymphotactin, OSM, KC/GRO, SCF, MIP-1? , MIP-2, TIMP-1, VEGF-A, MCP-1, MCP-3, and MCP-5. Our results showed that concentrations of most mediators in exudates and plasma reached peak levels on day 1 and were significantly reduced on day 3. Conversely, M? numbers started to increase on day 1 and reached peak levels on day 3. Moreover, LPS treatment in vitro significantly induced mediator productions in cell culture media and lysates from M? isolated on day 3. Our results also showed that on day 0, concentrations of many mediators in plasma were higher than those in exudates, whereas on day 1, the trend was reversed. Overall, the findings from thioglycollate elicited peritonitis reveal that reversible chemotactic gradients between peritoneal exudates and blood exist in basal and inflamed conditions and the inflammatory mediator production in vivo is disassociated with macrophage accumulation during inflammation resolution. PMID:23606798

Lam, Derek; Harris, Devon; Qin, Zhenyu

2013-03-31

264

Inflammatory Mediator Profiling Reveals Immune Properties of Chemotactic Gradients and Macrophage Mediator Production Inhibition during Thioglycollate Elicited Peritoneal Inflammation  

PubMed Central

Understanding of spatiotemporal profiling of inflammatory mediators and their associations with M? accumulation is crucial to elucidate the complex immune properties. Here, we used murine thioglycollate elicited peritonitis to determine concentrations of 23 inflammatory mediators in peritoneal exudates and plasma before (day 0) and after (days 1 and 3) thioglycollate administration to peritoneal cavities; these mediators included TNF-?, FGF-9, IFN-?, IP-10, RANTES, IL-1?, IL-6, IL-7, IL-10, IL-11, IL-12p70, IL-17A, lymphotactin, OSM, KC/GRO, SCF, MIP-1?, MIP-2, TIMP-1, VEGF-A, MCP-1, MCP-3, and MCP-5. Our results showed that concentrations of most mediators in exudates and plasma reached peak levels on day 1 and were significantly reduced on day 3. Conversely, M? numbers started to increase on day 1 and reached peak levels on day 3. Moreover, LPS treatment in vitro significantly induced mediator productions in cell culture media and lysates from M? isolated on day 3. Our results also showed that on day 0, concentrations of many mediators in plasma were higher than those in exudates, whereas on day 1, the trend was reversed. Overall, the findings from thioglycollate elicited peritonitis reveal that reversible chemotactic gradients between peritoneal exudates and blood exist in basal and inflamed conditions and the inflammatory mediator production in vivo is disassociated with macrophage accumulation during inflammation resolution.

Lam, Derek; Harris, Devon

2013-01-01

265

Electron Transport Chain Activity in Normal and Activated Rat Macrophages  

Microsoft Academic Search

The pivotal role played by the macrophage in specific and nonspecific immunity suggests that the physiological status of the macrophage may effect the overall regulation of the host defense system. Many studies have evaluated macrophages as effector cells by examining expression of surface markers, cytokine release, or tumor killing in the presence of challenge to host defenses. In this report,

Jonathan S. Reichner; James A. Mulligan; Henry C. Bodenheimer

1995-01-01

266

Epithelial cells and macrophages in myasthenia gravis thymus culture.  

PubMed

Monolayer culture of thymic nonlymphoid cells derived from female patients with myasthenia gravis (MG) and individuals who underwent heart surgery was established to investigate the cellular composition of the thymic microenvironment and the interaction of nonlymphoid cells with autologous thymocytes. Thymic epithelial cells were identified by immunoperoxidase staining using monoclonal antibodies (mAbs) specific for cytokeratin and MR6 and MR19 antigens expressed on cortical and medullary epithelial cells, respectively. Macrophages were characterized by determination of alpha-naphthyl acetate esterase activity and detection of M1 antigen by mAb. It was demonstrated that in MG thymus cultures the number of cortical MR6+ epithelial cells is significantly reduced, and the ability of the remaining MR6+ cells to bind autologous thymocytes is markedly affected. On the other hand, the number of macrophages and the interaction of those cells with thymocytes were similar in MG and control thymus cultures. Since MR6+ epithelial cells are numerically and functionally affected in MG, maturational events of T cells occurring in the inner cortex may be altered. The mechanisms underlying the induction and expansion of T helper clones in MG are discussed. PMID:2390810

Popeskovic, L; Apostolski, S; Isakovic, K

1990-09-01

267

Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response  

PubMed Central

In this study we investigated whether berberine-mediated induction of interleukin-12 (IL-12) production in antigen-presenting cells could regulate a cytokine profile of antigen-primed CD4+ T helper (Th) cells. Pretreatment with berberine induced IL-12 production in both macrophages and dendritic cells, and significantly increased the levels of IL-12 production in lipopolysaccharide-stimulated macrophages and in CD40 ligand-stimulated dendritic cells. Importantly, berberine pretreatment of macrophages increased their ability to induce interferon-? (IFN-?) and reduced their ability to induce IL-4 in antigen-primed CD4+ T cells. Berberine did not influence the macrophage cell surface expression of the class II major histocompatibility complex molecule, the co-stimulatory molecules CD80 and CD86, and intracellular adhesion molecule-1. Addition of neutralizing anti-IL-12p40 monoclonal antibody to cultures of berberine-pretreated macrophages and CD4+ T cells restored IL-4 production in antigen-primed CD4+ T cells. The in vivo administration of berberine resulted in the enhanced induction of IL-12 production by macrophages when stimulated in vitro with lipopolysaccharide or heat-killed Listeria monocytogenes, leading to the inhibition of the Th type 2 cytokine profile (decreased IL-4 and increased IFN-? production) in antigen-primed CD4+ T cells. These findings may point to a possible therapeutic use of berberine or medicinal plants containing berberine in the Th type 2 cell-mediated immune diseases such as allergic diseases.

Kim, Tae S; Kang, Bok Y; Cho, Daeho; Kim, Seung H

2003-01-01

268

THE EFFECT OF CYTOTOXIC AGENTS ON THE PASSIVE TRANSFER OF CELL-MEDIATED IMMUNITY  

PubMed Central

A system involving the passive transfer of committed lymphoid cells from Listeria-immune donors has been used to study the phases of the immune response which are sensitive to the immunosuppressive action of various cytotoxic agents. The agents investigated included cyclophosphamide, vinblastine, methotrexate, azathioprine, and X-irradiation. Complete suppression of passive immunization was obtained by the administration of cyclophosphamide or vinblastine to recipients at the time of cell transfer or by prior X-irradiation of recipients a day before cell transfer. Methotrexate was only partially suppressive, whereas azathioprine had no effect at all. The donor cell responsible for the transfer of immunity to recipients was shown to be a resting cell which is sensitive to the action of cyclophosphamide but not to vinblastine. The results of this investigation suggest that the donor cells undergo multiplication in the tissues of the recipient, presumably in response to specific stimulation by Listeria antigens. This in turn results in the activation of host macrophages. The immunosuppressive action of cyclophosphamide, vinblastine, and irradiation in the cell-transfer system has been discussed in relation to a direct cytotoxic action on the immune lymphoid cells of the donor and specific interference with their proliferation in the recipient, as well as impairment of macrophage production on the part of the recipient itself.

Tripathy, S. P.; Mackaness, G. B.

1969-01-01

269

Conditioned medium from alternatively activated macrophages induce mesangial cell apoptosis via the effect of Fas.  

PubMed

During inflammation in the glomerulus, the proliferation of myofiroblast-like mesangial cells is commonly associated with the pathological process. Macrophages play an important role in regulating the growth of resident mesangial cells in the glomeruli. Alternatively activated macrophage (M2 macrophage) is a subset of macrophages induced by IL-13/IL-4, which is shown to play a repair role in glomerulonephritis. Prompted by studies of development, we performed bone marrow derived macrophage and rat mesangial cell co-culture study. Conditioned medium from IL-4 primed M2 macrophages induced rat mesangial cell apoptosis. The pro-apoptotic effect of M2 macrophages was demonstrated by condensed nuclei stained with Hoechst 33258, increased apoptosis rates by flow cytometry analysis and enhanced caspase-3 activation by western blot. Fas protein was up-regulated in rat mesangial cells, and its neutralizing antibody ZB4 partly inhibited M2 macrophage-induced apoptosis. The up-regulated arginase-1 expression in M2 macrophage also contributed to this apoptotic effect. These results indicated that the process of apoptosis triggered by conditioned medium from M2 macrophages, at least is partly conducted through Fas in rat mesangial cells. Our findings provide compelling evidence that M2 macrophages control the growth of mesangial cells in renal inflammatory conditions. PMID:23973665

Huang, Yuan; Luo, Fangjun; Li, Hui; Jiang, Tao; Zhang, Nong

2013-08-23

270

Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation.  

PubMed

Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation. PMID:24146768

Zhou, Chao; Lei, Han; Chen, Yaxi; Liu, Qing; Li, Lung-Chih; Moorhead, John F; Varghese, Zac; Ruan, Xiong Z

2013-10-16

271

Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation  

PubMed Central

Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation.

Zhou, Chao; Lei, Han; Chen, Yaxi; Liu, Qing; Li, Lung-Chih; Moorhead, John F.; Varghese, Zac; Ruan, Xiong Z.

2013-01-01

272

Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells  

Microsoft Academic Search

Definitive erythropoiesis usually occurs in the bone marrow or fetal liver, where erythroblasts are associated with a central macrophage in anatomical units called `blood islands'. Late in erythropoiesis, nuclei are expelled from the erythroid precursor cells and engulfed by the macrophages in the blood island. Here we show that the nuclei are engulfed by macrophages only after they are disconnected

Hideyuki Yoshida; Kohki Kawane; Masato Koike; Yoshimi Mori; Yasuo Uchiyama; Shigekazu Nagata

2005-01-01

273

[Cannabinoids and the immune system. Of men, mice and cells].  

PubMed

The medical use of cannabis or cannabinoid compounds is controversial. Cannabinoids like the Delta(9)-THC (tetrahydrocannabinol) or the synthetic derivative Nabilone are available against cancer- and HIV-associated cachexia, nausea and vomiting. Over the last 20 years, the cannabinoid receptors CB(1) and CB(2) and their endogenous ligands have been found. The involvement of this endogenous cannabinoid signalling system in feeding, appetite, pain perception and immunomodulation could be demonstrated using animal and in vitro studies. Thus, the concern about immunosuppressive effects in humans using medical cannabinoid preparations grew. However, up to now most human studies have failed to demonstrate a well-defined and reproducible immunosuppressive cannabinoid-effect. Only the smoking of marijuana showed a significant local immunosuppression of the bactericidal activity of human alveolar macrophages. In animal studies, cannabinoids were identified as potent modulators of cytokine production, causing a shift from Th1 to Th2 cytokines. In consequence, a compromised cellular immunity was observed in these animals, resulting in enhanced tumor growth and reduced immunity to viral infections. In vitro, immunosuppressive effects were shown in all immune cells, but only at high micromolar cannabinoid concentrations not reached under normal clinical conditions. In conclusion, there is no evidence that cannabinoids induce a serious, relevant immunosuppression in humans, with the exception of marijuana-smoking which may affect local broncho-alveolar immunity. PMID:15221424

Kraft, B; Kress, H G

2004-06-01

274

Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development.  

PubMed

Developmental tissues go through regression, remodeling, and apoptosis. In these processes, macrophages phagocytize dead cells and induce apoptosis directly. In hyaloid vascular system (HVS), macrophages induce apoptosis of vascular endothelial cells (VECs) by cooperation between the Wnt and angiopoietin (Ang) pathways through cell-cell interaction. However, it remains unclear how macrophages are activated and interact with VECs. Here we show that Ninjurin1 (nerve injury-induced protein; Ninj1) was temporally increased in macrophages during regression of HVS and these Ninj1-expressing macrophages closely interacted with hyaloid VECs. Systemic neutralization using an anti-Ninj1 antibody resulted in the delay of HVS regression in vivo. We also found that Ninj1 increased cell-cell and cell-matrix adhesion of macrophages. Furthermore, Ninj1 stimulated the expression of Wnt7b in macrophages and the conditioned media from Ninj1-overexpressing macrophages (Ninj1-CM) decreased Ang1 and increased Ang2 in pericytes, which consequently switched hyaloid VEC fate from survival to death. Collectively, these findings suggest that macrophages express Ninj1 to increase the death signal through cell-cell interaction and raise the possibility that Ninj1 may act similarly in other developmental regression mediated by macrophages. PMID:19557008

Lee, H-J; Ahn, B J; Shin, M W; Jeong, J-W; Kim, J H; Kim, K-W

2009-06-26

275

Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance  

PubMed Central

Mammalian innate immune cells produce reactive oxygen species (ROS) in the oxidative burst reaction to destroy invading microbial pathogens. Using quantitative real-time ROS assays, we show here that both yeast and filamentous forms of the opportunistic human fungal pathogen Candida albicans trigger ROS production in primary innate immune cells such as macrophages and dendritic cells. Through a reverse genetic approach, we demonstrate that coculture of macrophages or myeloid dendritic cells with C. albicans cells lacking the superoxide dismutase (SOD) Sod5 leads to massive extracellular ROS accumulation in vitro. ROS accumulation was further increased in coculture with fungal cells devoid of both Sod4 and Sod5. Survival experiments show that C. albicans mutants lacking Sod5 and Sod4 exhibit a severe loss of viability in the presence of macrophages in vitro. The reduced viability of sod5?/? and sod4?/?sod5?/? mutants relative to wild type is not evident with macrophages from gp91phox?/? mice defective in the oxidative burst activity, demonstrating a ROS-dependent killing activity of macrophages targeting fungal pathogens. These data show a physiological role for cell surface SODs in detoxifying ROS, and suggest a mechanism whereby C. albicans, and perhaps many other microbial pathogens, can evade host immune surveillance in vivo.

Frohner, Ingrid E; Bourgeois, Christelle; Yatsyk, Kristina; Majer, Olivia; Kuchler, Karl

2009-01-01

276

Plasmacytoid dendritic cells play a major role in apoptotic leukocyte-induced immune modulation.  

PubMed

Several APCs participate in apoptotic cell-induced immune modulation. Whether plasmacytoid dendritic cells (PDCs) are involved in this process has not yet been characterized. Using a mouse model of allogeneic bone marrow engraftment, we demonstrated that donor bone marrow PDCs are required for both donor apoptotic cell-induced engraftment and regulatory T cell (Treg) increase. We confirmed in naive mice receiving i.v. syngeneic apoptotic cell infusion that PDCs from the spleen induce ex vivo Treg commitment. We showed that PDCs did not interact directly with apoptotic cells. In contrast, in vivo macrophage depletion experiments using clodronate-loaded liposome infusion and coculture experiments with supernatant from macrophages incubated with apoptotic cells showed that PDCs required macrophage-derived soluble factors--including TGF-?--to exert their immunomodulatory functions. Overall, PDCs may be considered as the major APC involved in Treg stimulation/generation in the setting of an immunosuppressive environment obtained by apoptotic cell infusion. These findings show that like other APCs, PDC functions are influenced, at least indirectly, by exposure to blood-borne apoptotic cells. This might correspond with an additional mechanism preventing unwanted immune responses against self-antigens clustered at the cell surface of apoptotic cells occurring during normal cell turnover. PMID:21460208

Bonnefoy, Francis; Perruche, Sylvain; Couturier, Mélanie; Sedrati, Abdeslem; Sun, Yunwei; Tiberghien, Pierre; Gaugler, Béatrice; Saas, Philippe

2011-04-01

277

Granulocyte-macrophage colony stimulating factor and lung immunity in pulmonary alveolar proteinosis  

Microsoft Academic Search

The anti-granulocyte-macrophage colony-stimulating factor (GM- CSF) autoantibody is inferred to cause idiopathic pulmonary alveo- larproteinosis(iPAP):theantibodyneutralizesGM-CSFandthereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully

Ryushi Tazawa; Emi Hamano; Toru Arai; Hiromitsu Ohta; Osamu Ishimoto; Kanji Uchida; Masato Watanabe; Junichi Saito; Miki Takeshita; Yasuhiko Hirabayashi; Ikuo Ishige; Yoshinobu Eishi; Koichi Hagiwara; Masahito Ebina; Yoshikazu Inoue; Koh Nakata; Toshihiro Nukiwa

2005-01-01

278

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.

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

2013-01-01

279

Cell-mediated immunity against connective tissue in experimental pulmonary fibrosis  

Microsoft Academic Search

Cell-mediated immunity against an extract of homologous normal lung connective tissue was determined in vitro in spleen cells\\u000a from CD1 mice with bleomycin-induced pulmonary fibrosis. Blastoid transformation and macrophage migration inhibitory factor\\u000a (MIF) were measured at intervals in spleen lymphocytes for a total of seven weeks after the initiation of the fibrogenic process.\\u000a MIF production was evident from the third

R. E. Carvajal; R. González; M. Selman

1982-01-01

280

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

281

Inhibitory receptor expression on neonatal immune cells.  

PubMed

Neonates are born with quantitative and qualitative defects in both adaptive and innate immune responses. The immune system is regulated by several mechanisms, including the signalling of inhibitory receptors. Increased expression of inhibitory receptors may result in a higher threshold for activation and suppressed function of neonatal cells. The aim of this study was to determine whether the expression of seven inhibitory receptors is increased on neonatal immune cells compared to adult immune cells. In a healthy birth cohort, we examined the expression of seven inhibitory immune receptors on neonatal neutrophils, monocytes, natural killer (NK) cells, CD4(+) and CD8(+)T cells. The expression of leucocyte-associated immunoglobulin (Ig)-like receptor-1 (LAIR-1), signal inhibitory receptor on leucocytes-1 (SIRL-1), CD31, signal-regulatory protein alpha (SIRP?), Siglec-9, CD200R, immune receptor expressed on myeloid cells-1 (IREM-1) and the membrane-bound ligand CD200 was studied by flow cytometry on leucocytes in cord blood (n = 14), neonatal venous blood (n = 24) and adult venous blood (n = 22). Expression of LAIR-1, CD31 and CD200 was increased consistently across all neonatal T cell subsets. Neonatal monocytes exhibited decreased expression of LAIR-1 and IREM-1 compared to adults. Furthermore, cord blood and neonatal venous blood samples contained a distinct LAIR-1-positive neutrophil population, which was not detected in adult blood. We demonstrated distinct expression of inhibitory receptors on neonatal peripheral blood immune cells in a healthy birth cohort. This is the first evidence that inhibitory receptors play a role in regulation of the neonatal immune system. Consistently increased inhibitory receptor expression on T cells may be an important mechanism in preventing the development of allergy and autoimmunity. PMID:22774991

Walk, J; Westerlaken, G H A; van Uden, N O; Belderbos, M E; Meyaard, L; Bont, L J

2012-08-01

282

The role of cystatins in cells of the immune system.  

PubMed

The cystatins constitute a large group of evolutionary related proteins with diverse biological activities. Initially, they were characterized as inhibitors of lysosomal cysteine proteases - cathepsins. Cathepsins are involved in processing and presentation of antigens, as well as several pathological conditions such as inflammation and cancer. Recently, alternative functions of cystatins have been proposed: they also induce tumour necrosis factor and interleukin 10 synthesis and stimulate nitric oxide production. The aim of the present review was the analysis of data on cystatins from NCBI GEO database and the literature, and obtained in microarray and serial analysis of gene expression (SAGE) experiments. The expression of cystatins A, B, C, and F in macrophages, dendritic cells and natural killer cells of the immune system, during differentiation and activation is discussed. PMID:17098233

Kopitar-Jerala, Natasa

2006-11-03

283

Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro.  

PubMed

An orphan G-protein-coupled receptor, T cell death-associated gene 8 (TDAG8) which has been reported to be a proton sensor, inhibits the production of pro-inflammatory cytokines induced by extracellular acidification. Recently, we have found that TDAG8 knockout mice showed significant exacerbation in various immune-mediated inflammation disease models. To elucidate the role of TDAG8, we screened an in-house library to find compounds which have a profile as a TDAG8 agonist using a cyclic adenosine 5'-monophosphate assay. Among the screening hits, we focused on (3-[(2,4-dichlorobenzyl)thio]-1,6-dimethyl-5,6-dihydro-1H-pyridazino[4,5-e][1,3,4]thiadiazin-5-one) (named BTB09089). BTB09089 did not act on other proton sensing G-protein-coupled receptors such as G-protein-coupled receptor 4 (GPR4) nor ovarian cancer G-protein-coupled receptor 1 (OGR1). Moreover, BTB09089 increased cAMP level in the splenocytes from wild-type littermates but not from TDAG8-deficient mice. Thus, BTB09089 was found to be a TDAG8 specific agonist. We then investigated the effects of BTB09089 on T cells and macrophages in vitro. In splenocytes, BTB09089 suppressed the production of IL-2 stimulated with anti-CD3 and anti-CD28 antibodies. In peritoneal exuded macrophages induced by thioglycollate, BTB09089 suppressed the production of TNF-? and IL-6 while it increased that of IL-10 when stimulated with lipopolysaccharide. These effects were observed in cells from wild type mice, but not those from TDAG8 knockout mice. These results indicate that activation of TDAG8 attenuates immune-mediated inflammation by regulating the cytokine production of T cells and macrophages. PMID:22445881

Onozawa, Yoshiko; Fujita, Yoshifumi; Kuwabara, Harumi; Nagasaki, Miyuki; Komai, Tomoaki; Oda, Tomiichiro

2012-03-15

284

Cell adhesion molecules in invertebrate immunity.  

PubMed

Cell adhesion is essential in immunity in invertebrates, e.g., in the cellular immune responses of encapsulation and nodule formation. Here cell adhesion molecules shown or suggested to be involved in invertebrate immunity are reviewed. Blood cells of the crayfish, Pacifastacus leniusculus, can release a cell-adhesive and opsonic peroxidase, peroxinectin. A site containing the motif, KGD, appears to be adhesive by binding to a transmembrane receptor of the integrin family on the blood cells. Peroxinectin also binds a peripheral blood cell surface CuZn-superoxide dismutase. The peroxidase-integrin interaction appears to have evolved early and seems conserved; human myeloperoxidase supports cell adhesion via the alphaMbeta2 integrin. There is evidence for peroxinectin-like proteins in other arthropods. Effects by RGD peptides indicate that integrins mediate blood cell adhesion and cellular immunity in diverse invertebrate species. Other invertebrate blood cell molecules proposed to be involved in adhesion include the insect plasmatocyte-spreading peptide, as well as soluble and transmembrane proteins which show some similarity to vertebrate adhesive or extracellular matrix molecules. Proteins such as the Ig family member hemolin, or proteins found in insects that are hosts for parasitic wasps, inhibit cell adhesion and may regulate or block cellular immunity. PMID:10426424

Johansson, M W

285

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

PubMed

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

2012-05-08

286

MicroRNAs in the regulation of immune cell functions--implications for atherosclerotic vascular disease.  

PubMed

Regarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNA-based strategies for therapies targeting inflammation and immunity in atherosclerosis. PMID:22318366

Zernecke, A

2012-02-08

287

Dynamics of Salmonella infection of macrophages at the single cell level  

PubMed Central

Salmonella enterica causes a range of diseases. Salmonellae are intracellular parasites of macrophages, and the control of bacteria within these cells is critical to surviving an infection. The dynamics of the bacteria invading, surviving, proliferating in and killing macrophages are central to disease pathogenesis. Fundamentally important parameters, however, such as the cellular infection rate, have not previously been calculated. We used two independent approaches to calculate the macrophage infection rate: mathematical modelling of Salmonella infection experiments, and analysis of real-time video microscopy of infection events. Cells repeatedly encounter salmonellae, with the bacteria often remain associated with the macrophage for more than ten seconds. Once Salmonella encounters a macrophage, the probability of that bacterium infecting the cell is remarkably low: less than 5%. The macrophage population is heterogeneous in terms of its susceptibility to the first infection event. Once infected, a macrophage can undergo further infection events, but these reinfection events occur at a lower rate than that of the primary infection.

Gog, Julia R.; Murcia, Alicia; Osterman, Natan; Restif, Olivier; McKinley, Trevelyan J.; Sheppard, Mark; Achouri, Sarra; Wei, Bin; Mastroeni, Pietro; Wood, James L. N.; Maskell, Duncan J.; Cicuta, Pietro; Bryant, Clare E.

2012-01-01

288

Croquemort, A Novel Drosophila Hemocyte\\/Macrophage Receptor that Recognizes Apoptotic Cells  

Microsoft Academic Search

Programmed cell death is first observed at stage 11 of embryogenesis in Drosophila. The systematic removal of apoptotic cells is mediated by cells that are derived from the procephalic mesoderm and differentiate into macrophages. We describe a macrophage receptor for apoptotic cells. This receptor, croquemort (catcher of death), is a member of the CD36 superfamily. Croquemort-mediated phagocytosis represents the concept

Nathalie C Franc; Jean-Luc Dimarcq; Marie Lagueux; Jules Hoffmann; R. Alan B Ezekowitz

1996-01-01

289

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

290

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

PubMed

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

2013-10-01

291

Francisella tularensis-infected macrophages release prostaglandin E2 that blocks T cell proliferation and promotes a Th2-like response.  

PubMed

Francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. In this study, we show that F. tularensis infection of macrophages alters T cell responses in vitro, by blocking T cell proliferation and promoting a Th2-like response. We demonstrate that a soluble mediator is responsible for this effect and identify it as PGE(2). Supernatants from F. tularensis-infected macrophages inhibited IL-2 secretion from both MHC class I and MHC class II-restricted T cell hybridomas, as well as enhanced a Th2-like response by inducing increased production of IL-5. Furthermore, the soluble mediator blocked proliferation of naive MHC class I-restricted T cells when stimulated with cognate tetramer. Indomethacin treatment partially restored T cell proliferation and lowered IL-5 production to wild-type levels. Macrophages produced PGE(2) when infected with F. tularensis, and treatment of infected macrophages with indomethacin, a cyclooxygenase-1/cyclooxygenase-2 inhibitor, blocked PGE(2) production. To further demonstrate that PGE(2) was responsible for skewing of T cell responses, we infected macrophages from membrane PGE synthase 1 knockout mice (mPGES1(-/-)) that cannot produce PGE(2). Supernatants from F. tularensis-infected membrane PGE synthase 1(-/-) macrophages did not inhibit T cell proliferation. Furthermore, treatment of T cells with PGE(2) recreated the effects seen with infected supernatant. From these data, we conclude that F. tularensis can alter host T cell responses by causing macrophages to produce PGE(2). This study defines a previously unknown mechanism used by F. tularensis to modulate adaptive immunity. PMID:17277110

Woolard, Matthew D; Wilson, Justin E; Hensley, Lucinda L; Jania, Leigh A; Kawula, Thomas H; Drake, James R; Frelinger, Jeffrey A

2007-02-15

292

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

293

Modulation of macrophage functions by sheeppox virus provides clues to understand interaction of the virus with host immune system  

PubMed Central

Background Poxviruses encode a range of immunomodulatory genes to subvert or evade the challenges posed by the innate and adaptive immune responses. However, the inactivated poxviruses possessed immunostimulating capacity and were used as a prophylactic or metaphylactic application that efficiently reduced susceptibility to infectious diseases in different species. This fact is intensively studied in different genera of poxviruses. However, little is known about the basic mechanisms adopted by sheeppox virus (SPPV). SPPV causes an acute disease of sheep that recently, has been observed to reinfect its host in spite of vaccination. Results By injecting inactivated or attenuated sheeppox virus SPPV vaccine in adult male Swiss mice, SPPV was found to reduce macrophages' functions in a local event that occurs at the site of application 12 h after vaccine administration as indicated by increased level of IL-10 and decreased level of SOD from cultured peritoneal macrophages. In contrast increased levels of IL-12, and SOD activity from cultured splenic macrophages, lymphocyte response to PHA-P, and in-vivo response to T-dependant Ag were detected. These effects were observed in both attenuated and inactivated SPPV, but more prominent in attenuated one. Conclusion The results of this study help to elucidate, the phenomenon of existence natural SPPV infections in sheep instead of vaccination and the basic mechanisms responsible for the immunostimulating capacity of sheeppox virus. Locally, SPPV shows evidence for an immune escape mechanism that alleviates the host's immune response. Later and systemically, the virus protects the host from any fatal consequences of the immune system suppression.

Abu-EL-Saad, Abdel-Aziz S; Abdel-Moneim, Ahmed S

2005-01-01

294

The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue.  

PubMed

The role of the immune system is to recognize pathogens, tumor cells or dead cells and to react with a very specific and localized response. By taking advantage of a highly sophisticated system of chemokines and chemokine receptors, leukocytes such as neutrophils, macrophages, and T-lymphocytes are targeted to the precise location of inflammation. While this is a beneficial process for acute infection and inflammation, recruitment of immune cells to sites of chronic inflammation can be detrimental. It is becoming clear that these inflammatory cells play a significant role in the initiation and progression of metabolic disorders such as atherosclerosis and insulin resistance by infiltrating the artery wall and adipose tissue (AT), respectively. Data from human studies indicate that elevated plasma levels of chemokines are correlated with these metabolic diseases. Recruitment of macrophages to the artery wall is well known to be one of the first steps in early atherosclerotic lesion formation. Likewise, recruitment of macrophages to AT is thought to contribute to insulin resistance associated with obesity. Based on this knowledge, much recent work in these areas has focused on the role of chemokines in attracting immune cells (monocytes/macrophages in particular) to these 2 sites. Thus, understanding the potential for chemokines to contribute to metabolic disease can help direct studies of chemokines as therapeutic targets. In this article, we will review current literature regarding the role of chemokines in atherosclerosis and obesity-related insulin resistance. We will focus on novel work showing that chemokine secretion from endothelial cells, platelets, and adipocytes can contribute to immune cell recruitment, with a diagram showing the time course of chemokine expression and leukocyte recruitment to AT. We will also highlight a few of the less-commonly known chemokine-chemokine receptor pairs. Finally, we will discuss the potential for chemokines as therapeutic targets for treatment of atherosclerosis and insulin resistance. PMID:20026286

Surmi, Bonnie K; Hasty, Alyssa H

2009-12-21

295

Cell-mediated Transfer of Catalase Nanoparticles from Macrophages to Brain Endothelial and Neural Cells  

PubMed Central

Background Our laboratories forged the concept of macrophage delivery of protein antioxidants to attenuate neuroinflammation and nigrostriatal degeneration in Parkinson’s disease (PD). Notably, the delivery of the redox enzyme, catalase, incorporated into a polyion complex micelle (“nanozyme”) by bone marrow-derived macrophages protected the nigrostriatal against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Nonetheless, how macrophage delivery of nanozyme increases the efficacy of catalase remains unknown. Methods Herein, we examined the transfer of nanozyme from macrophages to brain microvessel endothelial cells, neurons and astrocytes. Results Facilitated transport of the nanozyme from macrophages to endothelial and neural target cells occurred through endocytosis-independent mechanisms that involved fusion of cellular membranes; macrophage bridging conduits; and nanozyme lipid coatings. Nanozyme transfer was operative across an artificial blood brain barrier and showed efficient reactive oxygen species decomposition. Conclusion This is the first demonstration that drug-loaded macrophages discharge particles to contiguous target cells for potential therapeutic brain enzyme delivery. The pathways for drug delivery shown may be used for the treatment of degenerative disorders of the nervous system.

Haney, Matthew J.; Zhao, Yuling; Li, Shu; Higginbotham, Sheila M.; Booth, Stephanie L.; Han, Huai-Yun; Vetro, Joseph A.; Mosley, R. Lee; Kabanov, Alexander V.; Gendelman, Howard E.; Batrakova, Elena V.

2011-01-01

296

Cellular interactions in bovine tuberculosis: release of active mycobacteria from infected macrophages by antigen-stimulated T cells  

PubMed Central

The outcome of Mycobacterium bovis infections depends on the interactions of infected macrophages with T lymphocytes. Several studies in humans and in mouse models have suggested an important role for cytotoxicity in the protective immune response to mycobacterial infections, and both CD4+ and CD8+ T cells have been shown to elicit appropriate cytolytic activity. The present study investigated in vitro interactions of T cells with M. bovis?infected macrophages in bovine tuberculosis. The results showed that following interaction with antigen?stimulated peripheral blood mononuclear cells (PBMC) from infected cattle, there was an increased presence of M. bovis in the extracellular compartment of infected macrophage cultures, as measured by incorporation of [3H]uracil into mycobacterial RNA. Furthermore, out of a panel of T?cell clones from infected cattle, it was found that a higher proportion of CD8+ clones produced an increase in the number of metabolically active extracellular M. bovis organisms compared with CD4+ clones. Finally, a positive correlation between percentage of antigen?dependent release of mycobacteria and total uracil uptake by M. bovis within culture systems was detected. This could be regarded as an indication of preferential intracellular control of mycobacteria by activated macrophages.

Liebana, E; Aranaz, A; Aldwell, F E; McNair, J; Neill, S D; Smyth, A J; Pollock, J M

2000-01-01

297

Hot water extract of the sclerotium of Polyporus rhinocerus Cooke enhances the immune functions of murine macrophages.  

PubMed

Treatment of hot water extract of the sclerotium of Polyporus rhinocerus (PRW) with murine macrophages including RAW 264.7 cell line and primary macrophages (PMs) could enhance their functional activities. These include a significant up-regulation of pinocytosis; an increase in the production of reactive oxygen species (ROS) and nitric oxide (NO); an increase in tumor necrosis factor alpha (TNF-alpha) production and inducible nitric oxide synthase (iNOS) expression in both RAW 264.7 cells and PMs. Cell surface receptors for yeast-derived beta-glucan, including Dectin-1, CR3, and TLR2, were determined by flow cytometry, and the expression of Dectin-1+ cells on the cell surface decreased in the responses of PMs to PRW. PRW increased phosphorylation of IkappaBalpha, which could trigger the nuclear factor kappa B (NF-kappaB) signal pathway for macrophage activation in RAW 264.7 cells. Therefore, the immunomodulatory effect of PRW could be mediated by macrophage activation via the NF-kappaB signal pathway. PMID:22135875

Guo, Cuixia; Wong, Ka-Hing; Cheung, Peter C K

2011-01-01

298

Adenosine A(2A) receptor activation supports an atheroprotective cholesterol balance in human macrophages and endothelial cells.  

PubMed

The adenosine A(2A) receptor (A(2A)R) plays an important role in the regulation of inflammatory and immune responses. Our previous work has demonstrated that A(2A)R agonists exhibit atheroprotective effects by increasing expression of reverse cholesterol transport proteins in cultured human macrophages. This study explores the impact of pharmacologic activation/inhibition and gene silencing of A(2A)R on cholesterol homeostasis in both THP-1 human monocytes/macrophages and primary human aortic endothelial cells (HAEC). THP-1 human monocytes/macrophages and HAEC exposed to the A(2A)R-specific agonist ATL313 exhibited upregulation of proteins responsible for cholesterol efflux: the ABCA1 and G1 transporters. Further, activation of A(2A)R led to upregulation of the cholesterol metabolizing enzyme P450 27-hydroxylase, accompanied by intracellular changes in level of oxysterols. We demonstrate that anti-atherogenic properties of A(2A)R activation are not limited to the regulation of lipid efflux in vasculature, but include protection from lipid overload in macrophages, particularly via suppression of the CD36 scavenger receptor. The reduced lipid accumulation manifests directly as a diminution in foam cell transformation. In THP-1 macrophages, either A(2A)R pharmacological blockade or gene silencing promote lipid accumulation and enhance foam cell transformation. Our pre-clinical data provides evidence suggesting that A(2A)R stimulation by ATL313 has the potential to be a viable therapeutic strategy for cardiovascular disease prevention, particularly in patients with elevated risk due to immune/inflammatory disorders. PMID:23168167

Voloshyna, Iryna; Carsons, Steven; Littlefield, Michael J; Rieger, Jayson M; Figler, Robert; Reiss, Allison B

2012-11-17

299

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

300

CELLS INVOLVED IN THE IMMUNE RESPONSE  

PubMed Central

Cells of the different lymphoid organs in the normal adult rabbit were investigated for their capacity to respond in vitro to a number of stimuli, such as phytohemagglutinin (PHA), anti-rabbit immunoglobulin antiserum (GARIG) and allogeneic and xenogeneic lymphoid cells, and for their capacity to adsorb radioactively-labeled anti-immunoglobulin antiserum. The bone marrow cells responded minimally to PHA, GARIG, and the allogeneic and xenogeneic stimuli. The thymus cells were unable to respond to stimulation with GARIG although they responded to the other stimuli. The cells of the other lymphoid organs tested responded to all the mitogenic agents, to varying degrees. On the basis of the results presented and the findings of other investigators, it is concluded that: 1. The response of the cells to GARIG indicates a potential capacity to mediate humoral immunity and requires the presence of immunoglobulin or immunoglobulin-like recognition sites on the cell surface. 2. The response of the cells to PHA and allogeneic and xenogeneic cells indicates a potential capacity to mediate cellular immunity and does not necessitate the presence of immunoglobulin-recognition sites on the cell surface. 3. The thymus in the normal adult rabbit consists of cells capable of mediating cellular immunity only. 4. The other lymphoid organs appear to possess cells capable of mediating humoral and cellular immunity.

Daguillard, Fritz; Richter, Maxwell

1969-01-01

301

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

302

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

303

Immunoregulatory Roles of IL10 in Innate Immunity: IL10 Inhibits Macrophage Production of IFN-g-Inducing Factors but Enhances NK Cell Production of IFN-g1  

Microsoft Academic Search

higher than that in wild-type (WT) mice. The results also suggested that the NK cell is the source of IFN-g that is primarily responsible for this alveolar Mf priming. To further study the roles of IL-10-inhibiting chitin-induced IFN-g production, we used spleen cell cultures. The experiments showed that IL-12, IL-18, and TNF-a, which were produced by chitin-stimulated Mf, contributed to

Yoshimi Shibata; L. Ann Foster; Masashi Kurimoto; Haruki Okamura; Reiko M. Nakamura; Katsuhide Kawajiri; J. Paul Justice; Michael R. Van Scott; Quentin N. Myrvik; W. James Metzger

304

Physiology and Endocrinology Symposium: role of immune cells in the corpus luteum.  

PubMed

The immune system is essential for optimal function of the reproductive system. The corpus luteum (CL) is an endocrine organ that secretes progesterone, which is responsible for regulating the length of the estrous cycle, and for the establishment and maintenance of pregnancy in mammals. This paper reviews literature that addresses 2 areas; i) how immune cells are recruited to the CL, and ii) how immune cells communicate with luteal cells to affect the formation, development, and regression of the CL. Immune cells, primarily recruited to the ovulatory follicle from lymphoid organs after the LH surge, facilitate ovulation and populate the developing CL. During the luteal phase, changes in the population of macrophages, eosinophils, neutrophils, and T lymphocytes occur at critical functional stages of the CL. In addition to their role in facilitating ovulation, immune cells may have an important role in luteal function. Evidence shows that cytokines secreted by immune cells modulate both luteotropic and luteolytic processes. However, the decision to pursue either function may depend on the environment provided by luteal cells. It is suggested that understanding the role immune cells play could lead to identification of new strategies to improve fertility in dairy cattle and other species. PMID:23422006

Walusimbi, S S; Pate, J L

2013-02-19

305

Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation.  

PubMed

The intestine and its immune system have evolved to meet the extraordinary task of maintaining tolerance to the largest, most complex and diverse microbial commensal habitat, while meticulously attacking and containing even minute numbers of occasionally incoming pathogens. While our understanding is still far from complete, recent studies have provided exciting novel insights into the complex interplay of the many distinct intestinal immune cell types as well as the discovery of entirely new cell subsets. These studies have also revealed how proper development and function of the intestinal immune system is dependent on its specific microbiota, which appears to have evolutionarily co-evolved. Here we review key immune cells that maintain intestinal homeostasis and, conversely, describe how altered function and imbalances may lead to inflammatory bowel disease (IBD). We highlight the latest developments within this field, covering the major players in IBD including intestinal epithelial cells, macrophages, dendritic cells, adaptive immune cells, and the newly discovered innate lymphoid cells, which appear of characteristic importance for immune function at mucosal surfaces. We set these mucosal immune pathways in the functional context of IBD risk genes where such insight is available. Moreover, we frame our discussion of fundamental biological pathways that have been elucidated in model systems in the context of results from clinical trials in IBD that targeted key mediators secreted by these cells, as an attempt of 'functional' appraisal of these pathways in human disease. PMID:24104886

Cader, M Zaeem; Kaser, Arthur

2013-11-01

306

Immunity to PRRSV: Double-edged sword  

Microsoft Academic Search

The immune system is a double-edged sword for porcine reproductive and respiratory syndrome virus (PRRSV) infection. On one edge PRRSV has a predilection for immune cells and the disease manifestations can be linked directly to changes in the immune system. PRRSV appears to replicate extensively, if not exclusively, in cells of the immune lineage, notably macrophages; the direct replication of

T. W. Molitor; E. M. Bautista; C. S. Choi

1997-01-01

307

Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte/macrophage functions.  

PubMed

We have shown that neem leaf glycoprotein (NLGP) inhibits the regulatory T cell (Tregs) induced suppression of tumoricidal functions of CD14(+)CD68(+) monocyte/macrophages (MO/M?) from human peripheral blood. Cytotoxic efficacy of MO/M? toward macrophage sensitive cells, U937, is decreased in presence of Tregs (induced), however, it was increased further by supplementation of NLGP in culture. Associated Treg mediated inhibition of perforin/granzyme B expression and nitric oxide release from MO/M? was normalized by NLGP. Altered status of signature cytokines, like, IL-12, IL-10, IL-6, TNF? from MO/M? under influence of Tregs is also rectified by NLGP. Tregs significantly enhanced the expression of altered marker, mannose receptor (CD206) on CD68(+) cells that was downregulated upon NLGP exposure. In addition to tumoricidal functions, antigen presenting ability of MO/M? is hampered by Treg induced downregulation of CD80, CD86 and HLA-ABC. NLGP upregulated these molecules in MO/M? even in the presence of Tregs. Treg mediated inhibition of MO/M? chemotaxis in contact dependent manner was also normalized partially by NLGP, where participation of CCR5 was documented. Overall results suggest that Treg influenced pro-tumor MO/M? functions are rectified in a significant extent by NLGP to create an anti-tumor immune environment. PMID:22210373

Chakraborty, Tathagata; Bose, Anamika; Goswami, Kuntal Kanti; Goswami, Shyamal; Chakraborty, Krishnendu; Baral, Rathindranath

2011-12-27

308

Adaptive Immune Features of Natural Killer Cells  

PubMed Central

In an adaptive immune response, naïve T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion following re-encounter with the same pathogen. Although Natural Killer cells traditionally have been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. In a mouse model of cytomegalovirus (MCMV) infection, we demonstrate that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1000-fold in the liver following infection. Following a contraction phase, Ly49H+ NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing “memory” NK cells rapidly degranulate and produce cytokines upon reactivation. Adoptive transfer of these NK cells into naïve animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal novel properties of NK cells previously attributed only to cells of the adaptive immune system.

Sun, Joseph C.; Beilke, Joshua N.; Lanier, Lewis L.

2009-01-01

309

molecular genetic assessment of chicken macrophage innate immunity: toll-like receptors, mechanisms of action, and kinetic transcriptome profile  

Microsoft Academic Search

Understanding the genetic regulation of host response governing disease resistance mechanisms is of primary importance for improving animal health and food safety. Many of the biological characteristics of the chicken make it an ideal organism for studies in immunology, evolution, agriculture, medicine and comparative functional analyses. Different cell lines or primary cells from the immune system generate different immune responses

Ceren Ciraci

2010-01-01

310

In Vivo Invasion of Head and Neck Squamous Cell Carcinoma Cells Does Not Require Macrophages  

PubMed Central

Invasion of tumor cells into the local stroma is an important component in cancer progression. Here we report studies of the in vivo invasion of head and neck squamous cell carcinoma (HNSCC) cells in response to applied gradients of a growth factor [epidermal growth factor (EGF)] and a chemokine (CXCL12), using orthotopic floor-of-mouth models. Analysis of the invading cells indicated that >75% of them were tumor cells, about 15% macrophages, and <10% were unidentified. Surprisingly, although macrophages invaded together with tumor cells, macrophage contributions were not required for HNSCC invasion. CXCL12-induced in vivo invasion of HNSCC cells was also observed and found to occur via a unidirectional transactivation of epidermal growth factor receptor (EGFR) through CXCR4. Inhibition of tumor necrosis factor-?–converting enzyme using TNF-? protease inhibitor-2 selectively inhibited CXCL12-induced invasion but not EGF-induced invasion, consistent with CXCL12 activation of EGFR via release of EGFR ligands.

Smirnova, Tatiana; Adomako, Alfred; Locker, Joseph; Van Rooijen, Nico; Prystowsky, Michael B.; Segall, Jeffrey E.

2011-01-01

311

Motif prediction to distinguish LPS-stimulated pro-inflammatory vs. antibacterial macrophage genes  

Microsoft Academic Search

BACKGROUND: Innate immunity is the first line of defence offered by host cells to infections. Macrophage cells involved in innate immunity are stimulated by lipopolysaccharide (LPS), found on bacterial cell surface, to express a complex array of gene products. Persistent LPS stimulation makes a macrophage tolerant to LPS with down regulation of inflammatory genes (\\

Rahul K Kollipara; Narayanan B Perumal

2010-01-01

312

Regulatory T cells, tumour immunity and immunotherapy  

Microsoft Academic Search

Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment

Weiping Zou

2006-01-01

313

Transfer of extracellular vesicles during immune cell-cell interactions  

PubMed Central

SUMMARY The transfer of molecules between cells during cognate immune cell interactions has been reported, and recently a novel mechanism of transfer of proteins and genetic material such as small RNA between T cells and APCs has been described, involving exchange of extracellular vesicles (EVs) during the formation of the immunological synapse (IS). EVs – a term that encompasses exosomes and microvesicles – have been implicated in cell-cell communication during immune responses associated with tumors, pathogens, allergies and autoimmune diseases. This review focuses on EV transfer as a mechanism for the exchange of molecules during immune cell-cell interactions.

Gutierrez-Vazquez, Cristina; Villarroya-Beltri, Carolina; Mittelbrunn, Maria; Sanchez-Madrid, Francisco

2013-01-01

314

Innate Immune Cells Induce Hemorrhage in Tumors during Thrombocytopenia  

PubMed Central

Platelets are crucial regulators of tumor vascular homeostasis and continuously prevent tumor hemorrhage through secretion of their granules. However, the reason for tumor bleeding in the absence of platelets remains unknown. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. Here, we investigated the role of the inflamed tumor microenvironment in the induction of tumor vessel injury in thrombocytopenic mice. Using s.c. injections of vascular endothelial growth factor or tumor necrosis factor-? combined with depletion of neutrophils, we demonstrate that enhancing the opening of endothelial cell junctions was not sufficient to cause bleeding in the absence of platelets; instead, induction of tissue hemorrhage in thrombocytopenia required recruitment of leukocytes. Immunohistology revealed that thrombocytopenia-induced tumor hemorrhage occurs at sites of macrophage and neutrophil accumulation. Mice deficient in ?2 or ?3 integrins, which have decreased neutrophil and/or macrophage infiltration in their tumor stroma, were protected from thrombocytopenia-induced tumor hemorrhage, indicating that, in the absence of platelets, stroma-infiltrating leukocytes induced tumor vessel injury. This injury was independent of reactive oxygen species generation and of complement activation, as suggested by the persistence of tumor hemorrhage in C3- and nicotinamide adenine dinucleotide phosphate oxidase-deficient thrombocytopenic mice. Our results show that platelets counteract tumor-associated inflammation and that the absence of this platelet function elicits vascular injuries by tumor-infiltrating innate immune cells.

Ho-Tin-Noe, Benoit; Carbo, Carla; Demers, Melanie; Cifuni, Stephen M.; Goerge, Tobias; Wagner, Denisa D.

2009-01-01

315

1Autoreactive pre-plasma cells break tolerance in the absence of regulation by dendritic cells and macrophages  

PubMed Central

The ability to induce antibody responses to pathogens while maintaining the quiescence of autoreactive cells is an important aspect of immune tolerance. During activation of Toll-like receptor-4 (TLR4), dendritic cells (DCs) and macrophages (MFs) repress autoantibody production through their secretion of IL-6 and soluble CD40L (sCD40L). These soluble mediators selectively repress B cells chronically exposed to antigen, but not naïve cells, suggesting a means to maintain tolerance during TLR4 stimulation, yet allow immunity. In this study, we identify TNF? as a third repressive factor, which together with IL-6 and CD40L, account for nearly all the repression conferred by DCs and MFs. Like IL-6 and sCD40L, TNF? did not alter B cell proliferation or survival. Rather, it reduced the number of antibody secreting cells. To address whether the soluble mediators secreted by DCs and MFs functioned in vivo, we generated mice lacking IL-6, CD40L and TNF?. Compared to wildtype mice, these mice showed prolonged anti-nuclear antibody responses following TLR4 stimulation. Further, adoptive transfer of autoreactive B cells into chimeric IL-6-/- × CD40L-/- × TNF?-/- mice showed that pre-plasma cells secreted autoantibodies independent of germinal center formation or extrafollicular foci. These data indicate that in the absence of genetic predisposition to autoimmunity, loss of endogenous IL-6, CD40L, and TNF? promotes autoantibody secretion during TLR4 stimulation.

Gilbert, Mileka R.; Wagner, Nikki J.; Jones, Shannon Z.; Wisz, Amanda B.; Roques, Jose R.; Krum, Kristen N.; Lee, Sang-Ryul; Nickeleit, Volker; Hulbert, Chrys; Thomas, James W.; Gauld, Stephen B.; Vilen, Barbara J.

2012-01-01

316

In vitro interactions between bacteria, osteoblast-like cells and macrophages in the pathogenesis of biomaterial-associated infections.  

PubMed

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

2011-09-13

317

Fine Tuning Inflammation at the Front Door: Macrophage Complement Receptor 3-mediates Phagocytosis and Immune Suppression for Francisella tularensis  

PubMed Central

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.

Curry, Heather M.; Leander, Rachel; Schlesinger, Larry S.

2013-01-01

318

Electrochemical biosensors for on-chip detection of oxidative stress from immune cells.  

PubMed

Seamless integration of biological components with electrochemical sensors is critical in the development of microdevices for cell analysis. The present paper describes the integration miniature Au electrodes next to immune cells (macrophages) in order to detect cell-secreted hydrogen peroxide (H(2)O(2)). Photopatterning of poly(ethylene glycol) (PEG) hydrogels was used to both immobilize horseradish peroxidase molecules onto electrodes and to define regions for cell attachment in the vicinity of sensing electrodes. Electrodes micropatterned in such a manner were enclosed inside poly(dimethylsiloxane) fluid conduits and incubated with macrophages. The cells attached onto the exposed glass regions in the vicinity of the electrodes and nowhere else on the non-fouling PEG hydrogel surface. A microfluidic device was converted into an electrochemical cell by placing flow-through Ag?AgCl reference and Pt wire counter electrodes at the outlet and inlet, respectively. This microdevice with integrated H(2)O(2)-sensing electrodes had sensitivity of 27 ?A?cm(2) mM with a limit of detection of 2 ?M. Importantly, this microdevice allowed controllable seeding of macrophages next to electrodes, activation of these cells and on-chip monitoring of H(2)O(2) release in real time. In the future, this biosensor platform may be utilized for monitoring of macrophage responses to pathogens or for the study of inflammatory signaling in micropatterned cell cultures. PMID:22007269

Yan, Jun; Pedrosa, Valber A; Enomoto, James; Simonian, Aleksandr L; Revzin, Alexander

2011-09-20

319

Analysis of expression of genes involved in immune response modulation in silent multipotent mesenchymal stromal cells.  

PubMed

The expression of some genes modulating the immune response was studied in multipotent mesenchymal stromal cells (MMSC) from the bone marrow of a healthy donor. Non-activated MMSC expressed IL-6 and IL-10, complement H factor, macrophage growth factor, prostaglandin E2 synthase, and indoleamine-2,3-dioxygenase. The expression of all these genes was higher in female MMSC. A close inverse relationship between IL-6 expression in MMSC and male donor age, close relationship between body weight index and fibroblast CFU concentration in female donor bone marrow and between indoleamine-2,3-dioxygenase and macrophage growth factor in MMSC from these donors were detected. The expression of the analyzed genes was higher in MMSC of donors who had no antibodies to cytomegalovirus, herpes simplex virus, and Epstein-Barr virus in the blood. The results demonstrate the MMSC regulation of immune reactions by MMSC at the cell and organism levels. PMID:22816094

Petinati, N A; Shipunova, I N; Bigildeyev, A E; Kuz'mina, L A; Momotyuk, K S; Parovichnikova, E N; Drize, N I; Savchenko, V G

2012-06-01

320

Lactobacillus casei HY7213 ameliorates cyclophosphamide-induced immunosuppression in mice by activating NK, cytotoxic T cells and macrophages.  

PubMed

Lactic acid bacteria (LAB) have recently attracted considerable attention as treatment options for immune diseases, the incidence of which has been increasing worldwide. The ability of tumor necrosis factor-? producing LAB isolated from cheese to inhibit NF-?B activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages was investigated. Among the tested LAB, Lactobacillus casei HY7213 inhibited NF-?B activation most potently. Therefore, we measured its immunopotentiating effect in cyclophosphamide (CP)-immunosuppressed mice. When HY7213 was orally administered for 5 or 15 d, it reversed the CP immunosuppressant effect by increasing body and spleen weights, blood red and white blood cells levels, and splenocyte and bone marrow cells counts. Treatment with CP in mice markedly reduced concanavalin A (ConA)-induced T cell proliferation to 54% compared to the normal group. Oral administration of HY7213 in CP-immunosuppressed mice reversed that value to 95% of the normal group on day 15. Furthermore, oral administration of HY7213 to CP-treated mice significantly enhanced the expression of IL-2 and IFN-? in ConA-induced splenic cytotoxic T cells, restored the CP-impaired phagocytosis of macrophage, and increased the cytotoxicity of natural killer (NK) and cytotoxic T cells derived from spleen and bone marrow against YAC-1. Based on these findings, we suggest that HY7213 may promote the recovery of immunosuppression caused by chemotherapeutic agents, such as CP, by activating NK cells, cytotoxic T cells and macrophages. PMID:23672525

Jang, Se-Eun; Joh, Eun-Ha; Ahn, Young-Tae; Huh, Chul-Sung; Han, Myung Joo; Kim, Dong-Hyun

2013-06-01

321

Invasion of Vero cells and induction of apoptosis in macrophages by pathogenic Leptospira interrogans are correlated with virulence.  

PubMed Central

Interactions of virulent Leptospira interrogans serovar icterohaemorrhagiae strain Verdun with Vero cells (African green monkey kidney fibroblasts) and a monocyte-macrophage-like cell line (J774A.1) were assayed by a double-fluorescence immunolabelling method. Infectivity profiles were investigated according to (i) the duration of contact between leptospires and eukaryotic cells and (ii) the number of in vitro passages after primary isolation from lethally infected guinea pigs. Comparative experiments were conducted with the corresponding high-passage avirulent variant and the saprophytic leptospire Leptospira biflexa Patoc I. In Vero cells, virulent leptospires were quickly internalized from 20 min postinfection, whereas avirulent and saprophytic strains remained extracellularly located. In addition, the virulent strain demonstrated an ability to actively invade the monocyte-macrophage-like J774A.1 cells during the early stages of contact and to induce programmed cell death, as shown by the detection of oligonucleosomes in a quantitative sandwich enzyme immunoassay. In both cellular systems, subsequent in vitro subcultures demonstrated a progressive decrease of the invasiveness, pointing out the necessity of using primocultures of Leptospira for virulence studies. Invasiveness of virulent leptospires was significantly inhibited with monodansylcadaverine, indicating that internalization was dependent on receptor-mediated endocytosis. Invasion of epithelial cells and induction of apoptosis in macrophages may be related to the pathogenicity of Leptospira, and both could contribute to its ability to survive in the host and to escape from the immune response.

Merien, F; Baranton, G; Perolat, P

1997-01-01

322

Probing Host Pathogen Cross-Talk by Transcriptional Profiling of Both Mycobacterium tuberculosis and Infected Human Dendritic Cells and Macrophages  

PubMed Central

Background Transcriptional profiling using microarrays provides a unique opportunity to decipher host pathogen cross-talk on the global level. Here, for the first time, we have been able to investigate gene expression changes in both Mycobacterium tuberculosis, a major human pathogen, and its human host cells, macrophages and dendritic cells. Methodology/Principal Findings In addition to common responses, we could identify eukaryotic and microbial transcriptional signatures that are specific to the cell type involved in the infection process. In particular M. tuberculosis shows a marked stress response when inside dendritic cells, which is in accordance with the low permissivity of these specialized phagocytes to the tubercle bacillus and to other pathogens. In contrast, the mycobacterial transcriptome inside macrophages reflects that of replicating bacteria. On the host cell side, differential responses to infection in macrophages and dendritic cells were identified in genes involved in oxidative stress, intracellular vesicle trafficking and phagosome acidification. Conclusions/Significance This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments.

Withers, Michael; Tanne, Antoine; Castagnoli, Paola Ricciardi; Gicquel, Brigitte; Stoker, Neil G.; Butcher, Philip D.; Foti, Maria; Neyrolles, Olivier

2008-01-01

323

Mast Cell Regulation of the Immune Response  

PubMed Central

Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions. This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression. A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor. However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production. The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.

2009-01-01

324

Pseudomonas aeruginosa Induces Type-III-Secretion-Mediated Apoptosis of Macrophages and Epithelial Cells  

Microsoft Academic Search

Pseudomonas aeruginosa is a gram-negative opportunistic pathogen that is cytotoxic towards a variety of eukaryotic cells. To investigate the effect of this bacterium on macrophages, we infected J774A.1 cells and primary bone-marrow-derived murine macrophages with the P. aeruginosa strain PA103 in vitro. PA103 caused type-III-secretion-dependent killing of macrophages withi n2ho finfection. Only a portion of the killing required the putative

ALAN R. HAUSER; JOANNE N. ENGEL

1999-01-01

325

Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species  

PubMed Central

The phagocyte NAPDH–oxidase complex consists of several phagocyte oxidase (phox) proteins, generating reactive oxygen species (ROS) upon activation. ROS are involved in the defense against microorganisms and also in immune regulation. Defective ROS formation leads to chronic granulomatous disease (CGD) with increased incidence of autoimmunity and disturbed resolution of inflammation. Because regulatory T cells (Tregs) suppress autoimmune T-cell responses and are crucial in down-regulating immune responses, we hypothesized that ROS deficiency may lead to decreased Treg induction. Previously, we showed that in p47phox-mutated mice, reconstitution of macrophages (Mph) with ROS-producing capacity was sufficient to protect the mice from arthritis. Now, we present evidence that Mph-derived ROS induce Tregs. In vitro, we showed that Mph ROS-dependently induce Treg, using an NADPH-oxidase inhibitor. This finding was confirmed genetically: rat or human CGD Mph with mutated p47phox or gp91phox displayed hampered Treg induction and T-cell suppression. However, basal Treg numbers in these subjects were comparable to those in controls, indicating a role for ROS in induction of peripheral Tregs. Induction of allogeneic delayed-type hypersensitivity with p47phox-mutated Mph confirmed the importance of Mph-derived ROS in Treg induction in vivo. We conclude that NAPDH oxidase activity in Mph is important for the induction of Tregs to regulate T cell-mediated inflammation.

Kraaij, Marina D.; Savage, Nigel D. L.; van der Kooij, Sandra W.; Koekkoek, Karin; Wang, Jun; van den Berg, J. Merlijn; Ottenhoff, Tom H. M.; Kuijpers, Taco W.; Holmdahl, Rikard; van Kooten, Cees; Gelderman, Kyra A.

2010-01-01

326

Antitumor Immunity and Cancer Stem Cells  

PubMed Central

Self-renewing cancer stem cells (CSC) capable of spawning more differentiated tumor cell progeny are required for tumorigenesis and neoplastic progression of leukemias and several solid cancers. The mechanisms by which CSC cause tumor initiation and growth are currently unknown. Recent findings that suggest a negative correlation between degrees of host immunocompetence and rates of cancer development raise the possibility that only a restricted minority of malignant cells, namely CSC, may possess the phenotypic and functional characteristics to evade host antitumor immunity. In human malignant melanoma, a highly immunogenic cancer, we recently identified malignant melanoma initiating cells (MMIC), a novel type of CSC, based on selective expression of the chemoresistance mediator ABCB5. Here we present evidence of a relative immune privilege of ABCB5+ MMIC, suggesting refractoriness to current immunotherapeutic treatment strategies. We discuss our findings in the context of established immunomodulatory functions of physiologic stem cells and in relation to mechanisms responsible for the downregulation of immune responses against tumors. We propose that the MMIC subset might be responsible for melanoma immune evasion and that immunomodulation might represent one mechanism by which CSC advance tumorigenic growth and resistance to immunotherapy. Accordingly, the possibility of an MMIC-driven tumor escape from immune-mediated rejection has important implications for current melanoma immunotherapy.

Schatton, Tobias; Frank, Markus H.

2010-01-01

327

Langerhans cells: critical regulators of skin immunity?  

Microsoft Academic Search

Langerhans cells (LC) are members of the heterogenous family of professional antigen presenting dendritic cells (DC). They are identified by the C-type lectin receptor Langerin and form a contiguous network in the epidermis. Consequently, LC are an integral part of the skin barrier to the environment and were considered to be critical inducers of skin immunity, whereas dermal DC were

Björn E Clausen; Junda M Kel

2010-01-01

328

Dendritic Cells Efficiently Induce Protective Antiviral Immunity  

Microsoft Academic Search

Cytotoxic T lymphocytes (CTL) are essential for effective immunity to various viral infections. Because of the high speed of viral replication, control of viral infections imposes demanding functional and qualitative requirements on protective T-cell responses. Dendritic cells (DC) have been shown to efficiently acquire, transport, and present antigens to naive CTL in vitro and in vivo. In this study, we

BURKHARD LUDEWIG; STEPHAN EHL; URS KARRER; BERNHARD ODERMATT; HANS HENGARTNER; ROLF M. ZINKERNAGEL

1998-01-01

329

Mechanism of Suppression of Cell-Mediated Immunity by Measles Virus  

Microsoft Academic Search

The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the

Christopher L. Karp; Maria Wysocka; Larry M. Wahl; Joseph M. Ahearn; Peter J. Cuomo; Barbara Sherry; Giorgio Trinchieri; Diane E. Griffin

1996-01-01

330

Alternatively activated macrophages in infection and autoimmunity  

Microsoft Academic Search

Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy

DeLisa Fairweather; Daniela Cihakova

2009-01-01

331

Lactobacilli and streptococci induce inflammatory chemokine production in human macrophages that stimulates Th1 cell chemotaxis  

Microsoft Academic Search

Macrophages have a central role in innate-immune responses to bacteria. In the present work, we show that infection of human macrophages with Gram-positive pathogenic Strep- tococcus pyogenes or nonpathogenic Lactobacillus rhamnosus GG enhances mRNA expression of in- flammatory chemokine ligands CCL2\\/monocyte chemoattractant protein-1 (MCP-1), CCL3\\/macro- phage-inflammatory protein-1 (MIP-1), CCL5\\/ regulated on activation, normal T expressed and secreted, CCL7\\/MCP-3, CCL19\\/MIP-3, and

Ville Veckman; Minja Miettinen; Sampsa Matikainen; Roberto Lande; Elena Giacomini; Eliana M. Coccia; Ilkka Julkunen

2003-01-01

332

Regulation of T lymphocyte trafficking into lymph nodes during an immune response by the chemokines macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta.  

PubMed

By virtue of their target cell specificity, chemokines have the potential to selectively recruit leukocyte subpopulations into sites of inflammation. Their role in regulation of T lymphocyte traffic into lymph nodes during the development of an immune response has not previously been explored. The sensitization phase of contact hypersensitivity induced by the hapten, dinitrofluorobenzene (DNFB) in the mouse was used as a model of T lymphocyte trafficking in response to antigenic stimulation. Rapid accumulation of CD8+ and CD4+ T cells in the draining lymph nodes was closely associated with strongly enhanced expression of macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta mRNAs and proteins. Mast cells accumulating in the nodes during DNFB sensitization were the predominant source of MIP-1 beta, whereas MIP-1 alpha was expressed by multiple cell types. Neutralization of these chemokines profoundly inhibited T lymphocyte trafficking into lymph nodes and altered the outcome of a subsequent challenge to DNFB. Thus, beta-chemokines regulate T lymphocyte emigration from the circulation into lymph nodes during an immune response and contribute significantly to the immunologic outcome. PMID:9820547

Tedla, N; Wang, H W; McNeil, H P; Di Girolamo, N; Hampartzoumian, T; Wakefield, D; Lloyd, A

1998-11-15

333

T Regulatory Cells in Primary Immune Deficiencies  

PubMed Central

Purpose of the review To summarize studies on the development and function of T regulatory cells in primary immune deficiencies. Recent findings Primary immune deficiencies are associated with high rates of autoimmunity. T regulatory (TR) cells, which are critical to the control of autoimmunity, appear involved in the pathogenesis of PID-related autoimmunity. A number of PIDs, including Omenn’s syndrome and Wiskott Aldrich Syndrome, have been associated with impaired production and/or function of thymus-derived (natural) TR cells. Recently defined primary immunodeficiencies, including Stim1 deficiency, IL-10 receptor deficiency, and xIAP deficiency, have been associated with defects in TR cells. De novo generated TR cells from peripheral CD4+ conventional T cells is impaired in the hyper IgE syndrome. Summary Gene defects underlying PIDs may also compromise the TR cell, leading to breakdown of peripheral tolerance.

Verbsky, James W.; Chatila, Talal A.

2012-01-01

334

Adoptive transfer of immunity from mice immunized with ribosomes or live yeast cells of Histoplasma capsulatum.  

PubMed

This investigation was designed to compare the role of lymphoid cells and immune serum in protective immunity induced by immunization with ribosomes or live yeast cells of Histoplasma capsulatum. Spleen cells, peritoneal cells, and serum from C3H mice immunized with Histoplasma ribosomes or live cells were transferred intravenously to separate groups of syngeneic recipients. All recipients along with a set of immunized and control mice were challenged intravenously with 4 x 10(6) yeast cells of H. capsulatum, and protection was assessed. Immunization with ribosomes or live cells provided 90 to 100% protection. Mice receiving filtered spleen cells or peritoneal cells from donors immunnized with live cells showed 90 to 100% protection; 80 to 90% protection was observed for mice receiving cells from ribosome-immunized donors. In contrast, no evidence of protection was seen in mice receiving serum from either live-cell- or ribosome-immunized mice. Peritoneal cells were far more efficient than spleen cells in adoptive transfer of immunity. The adoptive immunity in recipients persisted for at least 3 weeks after transfer, the longest period tested in the present study. These results indicate that the immunity elicited by immunization with Histoplasma ribosomes or live cells is mediated by a cellular mechanism. PMID:870432

Tewari, R P; Sharma, D; Solotorovsky, M; Lafemina, R; Balint, J

1977-03-01

335

Palmitate- and lipopolysaccharide-activated macrophages evoke contrasting insulin responses in muscle cells.  

PubMed

Factors secreted by macrophages contribute to whole body insulin resistance, acting in part on adipose tissue. Muscle is the major tissue for glucose disposal, but how macrophage-derived factors impact skeletal muscle glucose uptake is unknown, or whether the macrophage environment influences this response. We hypothesized that conditioned medium from macrophages pretreated with palmitate or LPS would directly affect insulin action and glucose uptake in muscle cells. L6-GLUT4myc myoblasts were exposed to conditioned medium from RAW 264.7 macrophages pretreated with palmitate or LPS. Conditioned medium from palmitate-treated RAW 264.7 macrophages inhibited myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation while activating JNK p38 MAPK, decreasing IkappaBalpha, and elevating inflammation markers. Surprisingly, and opposite to its effects on adipose cells, conditioned medium from LPS-treated macrophages stimulated myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation without affecting stress kinases or inflammation indexes. This medium had markedly elevated IL-10 levels, and IL-10, alone, potentiated insulin action in myoblasts and partly reversed the insulin resistance imparted by medium from palmitate-treated macrophages. IL-10 neutralizing antibodies blunted the positive influence of LPS macrophage-conditioned medium. We conclude that myoblasts and adipocytes respond differently to cytokines. Furthermore, depending on their environment, macrophages negatively or positively influence muscle cells. Macrophages exposed to palmitate produce a mixture of proinflammatory cytokines that reduce insulin action in muscle cells; conversely, LPS-activated macrophages increase insulin action, likely via IL-10. Macrophages may be an integral element in glucose homeostasis in vivo, relaying effects of circulating factors to skeletal muscle. PMID:18840759

Samokhvalov, Victor; Bilan, Phillip J; Schertzer, Jonathan D; Antonescu, Costin N; Klip, Amira

2008-10-07

336

Depression of afferent arc of the in vivo cytotoxic T-cell immunity by bacterial lipopolysaccharides  

SciTech Connect

The afferent arc of the in vivo cytotoxic T-cell immunity assessed by second set rejection of ascitic allogeneic tumors was shown to be depressed by bacterial lipopolysaccharide (LPS) that was administered simultaneously with or 1 day before injection of allogeneic spleen cells as stimulators. Two different LPSs from Escherichia coli O55 and Klebsiella O3 displayed similar activities whereas dextran sulfate, concanavalin A, or poly A:U was not effective. Stimulator activities of allogeneic cells was not directly modified by LPS. Any definite suppressor activity on afferent or efferent arc of the T-cell response was not demonstrable in mice receiving LPS and allogeneic cells. Further, the LPS effect for immune depression was not diminished by whole body X-ray irradiation to the recipient at 300 R, which ablated the B-cell reactivity to LPS for polyclonal activation, or by treatment of the recipient with carrageenan, a known toxic agent to macrophages. It was suggested from these results that LPS suppresses the cytotoxic T-cell immunity by modulating responder T cells to be temporarily refractory to the allogeneic stimulus rather than by activating suppressor cells such as radiation-sensitive lymphocytes and carrageenan-sensitive macrophages.

Mizoguchi, K.; Nakashima, I.; Hasegawa, Y.; Isobe, K.; Kato, N.; Shimokata, K.; Kawashima, K.; Nagase, F.; Ando, K.; Yoshida, T.

1985-10-15

337

Francisella tularensis and Cell-Mediated Immunity in Man.  

National Technical Information Service (NTIS)

Protective immunity to Francisella turlarensis in man and other mammals depends on the presence of cell mediated immunity, whereas humoral immunity is less important. Tularemia or vaccination with the live vaccine strain of F. tularensis (F. tularensis LV...

G. Sandstroem

1988-01-01

338

Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-? Mediated Activation of Na?ve Macrophages  

PubMed Central

Background Macrophages infected with Mycobacterium tuberculosis (M.tb) are known to be refractory to IFN-? stimulation. Previous studies have shown that M.tb express components such as the 19-kDa lipoprotein and peptidoglycan that can bind to macrophage receptors including the Toll-like receptor 2 resulting in the loss in IFN-?responsiveness. However, it is unclear whether this effect is limited to infected macrophages. We have previously shown that M.tb-infected macrophages release exosomes which are 30–100 nm membrane bound vesicles of endosomal origin that function in intercellular communication. These exosomes contain mycobacterial components including the 19-kDa lipoprotein and therefore we hypothesized that macrophages exposed to exosomes may show limited response to IFN-? stimulation. Methodology/Principal Findings Exosomes were isolated from resting as well as M.tb-infected RAW264.7 macrophages. Mouse bone marrow-derived macrophages (BMMØ) were treated with exosomes +/? IFN-?. Cells were harvested and analyzed for suppression of IFN-? responsive genes by flow cytometry and real time PCR. We found that exosomes derived from M.tb H37Rv-infected but not from uninfected macrophages inhibited IFN-? induced MHC class II and CD64 expression on BMMØ. This inhibition was only partially dependent on the presence of lipoproteins but completely dependent on TLR2 and MyD88. The exosomes isolated from infected cells did not inhibit STAT1 Tyrosine phosphorylation but down-regulated IFN-? induced expression of the class II major histocompatibity complex transactivator; a key regulator of class II MHC expression. Microarray studies showed that subsets of genes induced by IFN-? were inhibited by exosomes from H37Rv-infeced cells including genes involved in antigen presentation. Moreover, this set of genes partially overlapped with the IFN-?-induced genes inhibited by H37Rv infection. Conclusions Our study suggests that exosomes, as carriers of M.tb pathogen associated molecular patterns (PAMPs), may provide a mechanism by which M.tb may exert its suppression of a host immune response beyond the infected cell.

Singh, Prachi P.; LeMaire, Christopher; Tan, John C.; Zeng, Erliang; Schorey, Jeffery S.

2011-01-01

339

Proinflammatory and prothrombotic effects on human vascular endothelial cells of Immune-cell-derived LIGHT  

PubMed Central

Objective LIGHT (TNFSF 14) belongs to the tumor necrosis factor superfamily and is expressed by activated T cells as well as various types of antigen presenting cells. LIGHT binds to its cellular receptors TR2 and LTßR and has a co-stimulatory role in T cell activation. Here, we compared the relative expression of LIGHT in different immune cells and the biological activity of immune cell-derived LIGHT on endothelial cells. Methods and Results Surface expression of LIGHT and mRNA production by PBMC and isolated T cells (CD4+ or CD8+) significantly increased after stimulation with PMA (Phorbolester-12-Myristat-13-Acetat) + ionomycin. No LIGHT expression on PMA stimulated monocytes or monocytic-like THP-1 cells could be detected; differentiation of monocytes and THP-1 cells into macrophages, however, resulted in up-regulation of LIGHT. Supernatants of stimulated T cells contained higher concentrations of soluble LIGHT than macrophage supernatants normalized to cell numbers; release of soluble LIGHT was found to be dependent on metalloproteinase activity. Size determination of released soluble LIGHT by size exclusion chromatography revealed a molecular mass of ~60 kDa, suggesting a trimeric form. Released soluble LIGHT induced expression of proinflammatory antigens ICAM-1, tissue factor and IL-8 in human endothelial cells and caused apoptosis of IFN-? pretreated endothelial cells. Soluble LIGHT was detected at low levels in sera of healthy controls and was significantly enhanced in sera of patients with chronic hepatitis C and rheumatoid arthritis (24.93 ± 9.41 vs.129.53 ± 49.14 and 172.13 ± 77.64; p < 0.0005). Conclusion These findings suggest that among immune cells activated T lymphocytes are the main source of soluble LIGHT with released amounts of soluble LIGHT markedly higher compared to platelets. Immune cell-derived membrane-bound and soluble trimeric LIGHT is biologically active, inducing proinflammatory changes in endothelial cells. Enhanced plasma levels of soluble LIGHT in patients with chronic infections suggest a role of LIGHT in systemic inflammatory activation.

2009-01-01

340

Effects of microwave exposure on the hamster immune system. III. Macrophage resistance to vesicular stomatitis virus infection  

SciTech Connect

Exposure of hamsters to microwave (MW) energy (2.45 GHz, 25 mW/cm2, 1 h) resulted in activation of peritoneal macrophages (PM) to a viricidal state restricting the replication of vesicular stomatitis virus (VSV). The PM from MW-exposed hamsters were viricidal as early as 1 day after exposure and remained active for 5 days. Immunization of hamsters with vaccinia virus induced viricidal PM by 3 to 4 days and they remained active for 7 days. To test the hypothesis that thermogenic MW exposure results in the release of endotoxin across the intestinal epithelium which subsequently activates PM, hamsters were injected with lipopolysaccharide (LPS) and their viricidal activity was studied. Lipopolysaccharide in vitro (0.2 microgram) and in vivo (0.5 microgram) activated macrophages to a viricidal state. When administered in vivo, LPS (0.5 microgram) activated macrophages as early as 1 day and the activity remained for 3 days. While MW exposure of PM in vitro failed to induce viricidal activity, exposure of PM to LPS in vitro induced strong viricidal activity. This suggests that the in vivo response of PM to MW is an indirect one, which is consistent with the hypothesis that MW-induced PM viricidal activity may be mediated via LPS. In preliminary experiments, MW exposure resulted in extended survival time for hamsters challenged with a lethal dose of vesicular stomatitis virus, supporting the concept that MW-activated PM may be a useful therapeutic modality.

Rao, G.R.; Cain, C.A.; Tompkins, W.A.

1984-01-01

341

Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation.  

PubMed

Macrophages undergo a wide spectrum of polarized activation states, and have the potential both to elicit tumor and tissue destructive reactions and to promote tumor progression (macrophage balance). In general, tumor-associated macrophages (TAM) from established tumors and the related myeloid-derived suppressor cells are diverse and have properties of M2-activated cells. As such, they help cancer progression and metastasis. Therefore, TAM are a key component of pathways connecting inflammation and cancer. PMID:19236898

Mantovani, Alberto; Sica, Antonio; Allavena, Paola; Garlanda, Cecilia; Locati, Massimo

2009-02-21

342

Both leukotoxin and poly- N-acetylglucosamine surface polysaccharide protect Aggregatibacter actinomycetemcomitans cells from macrophage killing  

Microsoft Academic Search

Two virulence factors produced by the periodontopathogen Aggregatibacter actinomycetemcomitans are leukotoxin, a secreted lipoprotein that kills human polymorphonuclear leukocytes and macrophages, and poly-N-acetylglucosamine (PGA), a surface polysaccharide that mediates intercellular adhesion, biofilm formation and detergent resistance. In this study we examined the roles of leukotoxin and PGA in protecting A. actinomycetemcomitans cells from killing by the human macrophage cell line

Vishwanath Venketaraman; Albert K. Lin; Amy Le; Scott C. Kachlany; Nancy D. Connell; Jeffrey B. Kaplan

2008-01-01

343

The Honeybee Antimicrobial Peptide Apidaecin Differentially Immunomodulates Human Macrophages, Monocytes and Dendritic Cells  

Microsoft Academic Search

We show that apidaecin binds to human macrophages, monocytes and dendritic cells, displaying different intracellular distributions and inducing diversified effects. An apidaecin-cell association was detectable at concentrations as low as 5 ?M and increased without saturation until 60 ?M, was receptor independent and required a physiological temperature (37°C). For apidaecin, cytosolic localization was prevalent in macrophages and endosomal localization in

Regina Tavano; Daniela Segat; Marina Gobbo; Emanuele Papini

2011-01-01

344

A comparative study: In vitro effects of EPA and DHA on immune functions of head-kidney macrophages isolated from large yellow croaker (Larmichthys crocea).  

PubMed

Comparative effects of different concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on immune responses of head-kidney macrophages isolated from large yellow croaker were studied in vitro. After exposing to serum-free medium for 1 day, cultured cells were incubated in medium supplemented with graded levels of EPA or DHA (0, 5, 25, 100, 200 and 1000 ?M, respectively) in the form of fatty acid bovine serum albumin (FA-BSA) complex for 12 h, 24 h and 36 h, respectively. Control samples were incubated in the absence of EPA or DHA (2% bovine serum albumin, BSA). Following stimulation, cell viability, lipid peroxidation, secretary phopholipase A2 (sPLA2) and prostaglandin E2 (PGE2) production as well as some immune parameters including phagocytosis, respiratory burst activity and interleukin 1? (IL-1?) production were determined. Results showed that EPA and DHA affected cell viability in dose-dependent and time-dependent manners. In particular, cell viability was significantly decreased after 24 h and 36 h incubation with 1000 ?M EPA or DHA (P < 0.05). Higher levels of EPA (200 and 1000 ?M) caused a significant increase in the production of malondialdehyde (MDA) (P < 0.05), while DHA did not significantly affect the MDA production. EPA significantly increased the intracellular superoxide anion synthesis which, on the contrary, was significantly reduced by DHA. Phagocytosis percentage (PP) values were significantly higher in treatments with 5 ?M DHA (P < 0.05), but significantly decreased by 200 and 1000 ?M EPA and DHA compared to the control group (P < 0.05). Decreased PGE2 production was produced by cells treated with relatively low doses of EPA or DHA. When high levels of stimulants (1000 ?M EPA or DHA) were used, PGE2 levels were elevated and reached a significant level (P < 0.05). Both EPA and DHA significantly inhibited the production of sPLA2, where DHA exerted the more potent inhibitory effects than EPA. No pronounced effect was observed on IL-1? production among all the treatments, and IL-1? level in cell culture supernatant was fairly low (only approximately 6 pg/ml). Those findings suggested that EPA and DHA could influence the immunity and physiological conditions of macrophages from head kidney of large yellow croaker in vitro. PMID:23859878

Li, Qingfei; Ai, Qinghui; Mai, Kangsen; Xu, Wei; Zheng, Yuefu

2013-07-13

345

Interleukin-4 induces foreign body giant cells from human monocytes/macrophages. Differential lymphokine regulation of macrophage fusion leads to morphological variants of multinucleated giant cells.  

PubMed Central

Interleukin-4 induced the formation of foreign body-type giant multinucleated cells from human monocyte-derived macrophages, an effect that was optimized with either granulocyte-macrophage colony-stimulating factor or interleukin-3, dependent on the concentration of interleukin-4, and specifically prevented by anti-interleukin-4. Very large foreign body giant cells and, predominantly, giant cell syncytia with randomly arranged nuclei and extensive cytoplasmic spreading (285 +/- 121 nuclei and 1.151 +/- 0.303 mm2 per syncytium) were consistently obtained. Under otherwise identical culture conditions, relatively much smaller Langhans-type giant cells with circularly arranged nuclei were induced with a previously described combination of interferon-gamma plus granulocyte-macrophage colony-stimulating factor or interleukin-3 (16 +/- 6 nuclei and 0.033 +/- 0.013 mm2 per giant cell); their formation was prevented by anti-interferon-gamma but not by anti-interleukin-4. Similar rates of macrophage fusion were obtained in both culture systems (72 +/- 5% and 74 +/- 6%, respectively), but these two morphological variants did not occur simultaneously or form from one another within the 10-day culture period. These findings demonstrate that interleukin-4 is a potent human macrophage fusion factor and that differential regulation of macrophage fusion by interleukin-4 and interferon-gamma may lead to morphological variants of multinucleated giant cells. Images Figure 1 Figure 4

McNally, A. K.; Anderson, J. M.

1995-01-01

346

Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis.  

PubMed

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 in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1beta, tumor necrosis factor alpha, or interferon gamma increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis. PMID:9050882

Mach, F; Schönbeck, U; Sukhova, G K; Bourcier, T; Bonnefoy, J Y; Pober, J S; Libby, P

1997-03-01

347

Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: Implications for CD40-CD40 ligand signaling in atherosclerosis  

PubMed Central

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 in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1?, tumor necrosis factor ?, or interferon ? increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.

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

1997-01-01

348

Effects of macrophage colony-stimulating factor on macrophages and their related cell populations in the osteopetrosis mouse defective in production of functional macrophage colony-stimulating factor protein.  

PubMed Central

The development of macrophage populations in osteopetrosis (op) mutant mice defective in production of functional macrophage colony-stimulating factor (M-CSF) and the response of these cell populations to exogenous M-CSF were used to classify macrophages into four groups: 1) monocytes, monocyte-derived macrophages, and osteoclasts, 2) MOMA-1-positive macrophages, 3) ER-TR9-positive macrophages, and 4) immature tissue macrophages. Monocytes, monocyte-derived macrophages, osteoclasts in bone, microglia in brain, synovial A cells, and MOMA-1- or ER-TR9-positive macrophages were deficient in op/op mice. The former three populations expanded to normal levels in op/op mice after daily M-CSF administration, indicating that they are developed and differentiated due to the effect of M-CSF supplied humorally. In contrast, the other cells did not respond or very slightly responded to M-CSF, and their development seems due to either M-CSF produced in situ or expression of receptor for M-CSF. Macrophages present in tissues of the mutant mice were immature and appear to be regulated by either granulocyte/macrophage colony-stimulating factor and/or interleukin-3 produced in situ or receptor expression. Northern blot analysis revealed different expressions of GM-CSF and IL-3 mRNA in various tissues of the op/op mice. However, granulocyte/macrophage colony-stimulating factor and interleukin-3 in serum were not detected by enzyme-linked immunosorbent assay. The immature macrophages differentiated and matured into resident macrophages after M-CSF administration, and some of these cells proliferated in response to M-CSF. Images Figure 4 Figure 6 Figure 8 Figure 10 Figure 11

Umeda, S.; Takahashi, K.; Shultz, L. D.; Naito, M.; Takagi, K.

1996-01-01

349

Fibrocyte-like cells recruited to the spleen support innate and adaptive immune responses to acute injury or infection  

PubMed Central

Bone marrow (BM)-derived fibrocytes are a population of CD45+ and collagen Type I-expressing cells that migrate to the spleen and to target injured organs, such as skin, lungs, kidneys, and liver. While CD45+Col+ fibrocytes contribute to collagen deposition at the site of injury, the role of CD45+Col+ cells in spleen has not been elucidated. Here, we demonstrate that hepatotoxic injury (CCl4), TGF-?1, lipopolysaccharide, or infection with Listeria monocytogenes induce rapid recruitment of CD45+Col+ fibrocyte-like cells to the spleen. These cells have a gene expression pattern that includes antimicrobial factors (myleoperoxidase, cathelicidin, and defensins) and MHC II at higher levels than found on quiescent or activated macrophages. The immune functions of these splenic CD45+Col+ fibrocyte-like cells include entrapment of bacteria into extracellular DNA-based structures containing cathelicidin and presentation of antigens to naïve CD8+ T cells to induce their proliferation. Stimulation of these splenic fibrocyte-like cells with granulocyte macrophage-colony stimulating factor or macrophage-colony stimulating factor induces downregulation of collagen expression and terminal differentiation into the dendritic cells or macrophage. Thus, splenic CD45+Col+ cells are a population of rapidly mobilized BM-derived fibrocyte-like cells that respond to inflammation or infection to participate in innate and adaptive immune responses.

von Kockritz-Blickwede, Maren; Reichart, Donna; McGillvray, Shauna M.; Wingender, Gerhard; Kronenberg, Mitchell; Glass, Christopher K.; Nizet, Victor; Brenner, David A.

2011-01-01

350

Combined chromatin and expression analysis reveals specific regulatory mechanisms within cytokine genes in the macrophage early immune response.  

PubMed

Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS).To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches--gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. PMID:22384210

Iglesias, Maria Jesus; Jesus Iglesias, Maria; Reilly, Sarah-Jayne; Emanuelsson, Olof; Sennblad, Bengt; Pirmoradian Najafabadi, Mohammad; Folkersen, Lasse; Mälarstig, Anders; Lagergren, Jens; Eriksson, Per; Hamsten, Anders; Odeberg, Jacob

2012-02-27

351

Combined Chromatin and Expression Analysis Reveals Specific Regulatory Mechanisms within Cytokine Genes in the Macrophage Early Immune Response  

PubMed Central

Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/?LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response.

Emanuelsson, Olof; Sennblad, Bengt; Pirmoradian Najafabadi, Mohammad; Folkersen, Lasse; Malarstig, Anders; Lagergren, Jens; Eriksson, Per; Hamsten, Anders; Odeberg, Jacob

2012-01-01

352

Studying the role of macrophages in circulating prostate cancer cells by in vivo flow cytometry  

NASA Astrophysics Data System (ADS)

Metastasis is a very complicated multi-step process and accounts for the low survival rate of the cancerous patients. To metastasize, the malignant cells must detach from the primary tumor and migrate to secondary sites in the body through either blood or lymph circulation. Macrophages appear to be directly involved in tumor progression and metastasis. However, the role of macrophages in affecting cancer metastasis has not been fully elucidated. Here, we have utilized an emerging technique, namely in vivo flow cytometry (IVFC) to study the depletion kinetics of circulating prostate cancer cells in mice and how depletion of macrophages by the liposome-encapsulated clodronate affects the depletion kinetics. Our results show different depletion kinetics of PC-3 cells between macrophage-deficient group and the control group. The number of circulating tumor cells (CTCs) in macrophage-deficient group decreases in a slower manner compared to the control mice group. The differences in depletion kinetics indicate that the absence of macrophages facilitates the stay of prostate cancer cells in circulation. We speculate that macrophages might be able to arrest, phagocytose and digest PC-3 cells. Therefore, the phagocytosis may mainly contribute to the depletion kinetic differences. The developed methods here would be useful to study the relationship between macrophages and tumor metastasis in small animal cancer model.

Cui, Xiaojun; Guo, Jin; Gu, Zhengqin; Wei, Xunbin

2012-12-01

353

n-3 Fatty acids uniquely affect anti-microbial resistance and immune cell plasma membrane organization  

PubMed Central

It is now well established that dietary lipids are incorporated into macrophage and T-cell membrane microdomains, altering their structure and function. Within cell membranes, there are specific detergent-resistant domains in which key signal transduction proteins are localized. These regions are classified as “lipid rafts”. Rafts are composed mostly of cholesterol and sphingolipids and therefore do not integrate well into the fluid phospholipid bilayers causing them to form microdomains. Upon cell activation, rafts compartmentalize signal-transducing molecules, thus providing an environment conducive to signal transduction. In this review, we discuss recent novel data describing the effects of n-3 PUFA on alterations in the activation and functions of macrophages and T-cells. We believe that the modifications in these two disparate immune cell types are linked by fundamentally similar changes in membrane lipid composition and transmembrane signaling functions. We conclude that the outcomes of n-3 PUFA-mediated immune cell alterations may be beneficial (e.g., anti-inflammatory) or detrimental (e.g., loss of microbial immunity) depending upon the cell type interrogated.

McMurray, David N.; Bonilla, Diana L.; Chapkin, Robert S.

2011-01-01

354

The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology.  

PubMed

Nuclear receptors are ligand-activated transcription factors linking lipid signaling to the expression of the genome. There is increasing appreciation of the involvement of this receptor network in the metabolic programming of macrophages and dendritic cells (DCs), essential members of the innate immune system. In this review we focus on the role of retinoid X receptor, retinoic acid receptor, peroxisome proliferator-associated receptor ?, liver X receptor, and vitamin D receptor in shaping the immune and metabolic functions of macrophages and DCs. We also provide an overview of the contribution of macrophage- and DC-expressed nuclear receptors to various immunopathologic conditions, such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, asthma, and some others. We suggest that systematic analyses of the roles of these receptors and their activating lipid ligands in immunopathologies combined with complementary and focused translational and clinical research will be crucial for the development of new therapies using the many molecules available to target nuclear receptors. PMID:23905916

Kiss, Mate; Czimmerer, Zsolt; Nagy, Laszlo

2013-08-01

355

Protection Against Type 1 Diabetes Upon Coxsackievirus B4 Infection and iNKT-Cell Stimulation: Role of Suppressive Macrophages.  

PubMed

Invariant natural killer T (iNKT) cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and participate in responses against different pathogens. They have been shown to prevent type 1 diabetes development and to promote antiviral responses. Many studies in the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. This study of the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that although infection accelerated type 1 diabetes development in a subset of proinsulin 2-deficient NOD mice, the activation of iNKT cells by a specific agonist, ?-galactosylceramide, at the time of infection inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages, producing high levels of interleukin (IL)-1?, IL-6, and tumor necrosis factor-? and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT-cell stimulation expressed a number of suppressive enzymes, among which indoleamine 2,3-dioxygenase was sufficient to inhibit anti-islet T-cell response and to prevent diabetes. This study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes. PMID:23894189

Ghazarian, Liana; Diana, Julien; Beaudoin, Lucie; Larsson, Pär G; Puri, Raj K; van Rooijen, Nico; Flodström-Tullberg, Malin; Lehuen, Agnès

2013-07-26

356

Macrophage Activation Redirects Yersinia-Infected Host Cell Death from Apoptosis to Caspase-1-Dependent Pyroptosis  

PubMed Central

Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and naïve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ? Yersinia pseudotuberculosis (Yptb). YopJ? Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis.

Bergsbaken, Tessa; Cookson, Brad T

2007-01-01

357

Expression of the Rous sarcoma virus src gene in avian macrophages fails to elicit transformed cell phenotype.  

PubMed Central

Infection of avian macrophages with Rous sarcoma virus does not induce any changes in the morphology, growth behavior, or expression of macrophage-specific proteins. The absence of cellular transformation does not result from a block in the synthesis of viral proteins, since infectious viruses are released from a majority of cells in the culture. In this report, we examine the synthesis, processing, and functional activity of pp60src in Rous sarcoma virus-infected macrophages to determine whether the absence of transformation is due to an alteration in the functional expression of pp60src. Although the absolute level of pp60src was reduced compared with fibroblasts, the protein exhibited the same phosphorylation pattern and subcellular distribution and was able to phosphorylate immunoglobulin in the immune complex-protein kinase assay. These results imply that the failure of Rous sarcoma virus to transform macrophage may be due to a restriction in the cellular response to a functional src protein, perhaps due to the absence of cellular products which are essential for mediating pp60src-induced transformation. Images

Lipsich, L; Brugge, J S; Boettiger, D

1984-01-01

358

Macrophages increase microparticle uptake by enterocyte-like Caco-2 cell monolayers  

PubMed Central

Caco-2 cells form an enterocyte-like monolayer that has been used to explore small intestinal microparticle uptake. They are a useful functional model for the investigation of in vivo drug delivery systems and the uptake of particulate environmental pollutants. The aim of this paper was to determine if the previously reported decrease in Caco-2 transepithelial resistance following exposure to macrophages was matched by increased microparticle uptake, especially as macrophage phagocytosis simulates removal of particles from the subepithelial compartment. Caco-2 cells were grown as a monoculture for 21 days on insert membranes. A compartmentalised model involved Caco-2 cells in the upper compartment, with THP-1-derived macrophages adhering to the base of the underlying well, the two cell populations communicating only through the shared culture medium. Caco-2 cells were also cultured in macrophage-conditioned medium and all groups were exposed apically to 2 ?m latex particles for 5 or 60 min. Parameters measured were: transepithelial resistance; cytokine levels; cell dimensions and the distribution of nuclei, actin and junctional proteins. Subepithelial particle numbers, defined as those located below the insert membrane, were also counted and were significantly increased in the Caco-2/macrophage model, with over 90% associated with the macrophages. Other changes induced by the presence of macrophages included decreased transepithelial resistance levels, diffuse localisation of some junctional proteins, higher proinflammatory cytokine levels, disorganisation of cell shape and decreased cell height associated with actin reorganisation. Macrophage-conditioned medium produced a smaller transepithelial resistance decrease than the Caco-2/macrophage model and there were few other changes. In conclusion, culture of Caco-2 cells with underlying macrophages produced a lower, less organised epithelium and greater microparticle uptake.

Moyes, Siobhan M; Morris, John F; Carr, Katharine E

2010-01-01

359

Imaging interactions of metal oxide nanoparticles with macrophage cells by ultra-high resolution scanning electron microscopy techniques.  

PubMed

Use of engineered metal oxide nanoparticles in a plethora of biological applications and custom products has warned about some possible dose-dependent cytotoxic effects. Macrophages are key components of the innate immune system used to study possible toxic effects and internalization of different nanoparticulate materials. In this work, ultra-high resolution field emission scanning electron microscopy (FE-SEM) was used to offer new insights into the dynamical processes of interaction of nanomaterials with macrophage cells dosed with different concentrations of metal oxide nanoparticles (CeO(2), TiO(2) and ZnO). The versatility of FE-SEM has allowed obtaining a detailed characterization of processes of adsorption and endocytosis of nanoparticles, by using advanced analytical and imaging techniques on complete unstained uncoated cells, including secondary electron imaging, high-sensitive backscattered electron imaging, X-ray microanalysis and stereoimaging. Low voltage BF/DF-STEM confirmed nanoparticle adsorption and internalization into endosomes of CeO(2) and TiO(2), whereas ZnO develop apoptosis after 24 h of interaction caused by dissolution and invasion of cell nucleus. Ultra-high resolution scanning electron microscopy techniques provided new insights into interactions of inorganic nanoparticles with macrophage cells with high spatial resolution. PMID:23023106

Plascencia-Villa, Germán; Starr, Clarise R; Armstrong, Linda S; Ponce, Arturo; José-Yacamán, Miguel

2012-11-01

360

Macrophage inflammatory protein-1? as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions  

PubMed Central

Regulation of the immune response requires the cooperation of multiple signals in the activation of effector cells. For example, T cells require signals emanating from both the TCR for antigen (upon recognition of MHC/antigenic peptide) and receptors for costimulatory molecules (e.g., CD80 and CD60) for full activation. Here we show that IgE-mediated reactions in the conjunctiva also require multiple signals. Immediate hypersensitivity reactions in the conjunctiva were inhibited in mice deficient in macrophage inflammatory protein–1? (MIP-1?) despite normal numbers of tissue mast cells and no decrease in the levels of allergen-specific IgE. Treatment of sensitized animals with neutralizing antibodies with specificity for MIP-1? also inhibited hypersensitivity in the conjunctiva. In both cases (MIP-1? deficiency and antibody treatment), the degranulation of mast cells in situ was affected. In vitro sensitization assays showed that MIP-1? is indeed required for optimal mast cell degranulation, along with cross-linking of the high-affinity IgE receptor, Fc?RI. The data indicate that MIP-1? constitutes an important second signal for mast cell degranulation in the conjunctiva in vivo and consequently for acute-phase disease. Antagonizing the interaction of MIP-1? with its receptor CC chemokine receptor 1 (CCR1) or signal transduction from CCR1 may therefore prove to be effective as an antiinflammatory therapy on the ocular surface.

Miyazaki, Dai; Nakamura, Takao; Toda, Masako; Cheung-Chau, Kam-Wa; Richardson, Ricardo M.; Ono, Santa Jeremy

2005-01-01

361

Macrophages Discriminate Glycosylation Patterns of Apoptotic Cell-derived Microparticles*  

PubMed Central

Inappropriate clearance of apoptotic remnants is considered to be the primary cause of systemic autoimmune diseases, like systemic lupus erythematosus. Here we demonstrate that apoptotic cells release distinct types of subcellular membranous particles (scMP) derived from the endoplasmic reticulum (ER) or the plasma membrane. Both types of scMP exhibit desialylated glycotopes resulting from surface exposure of immature ER-derived glycoproteins or from surface-borne sialidase activity, respectively. Sialidase activity is activated by caspase-dependent mechanisms during apoptosis. Cleavage of sialidase Neu1 by caspase 3 was shown to be directly involved in apoptosis-related increase of surface sialidase activity. ER-derived blebs possess immature mannosidic glycoepitopes and are prioritized by macrophages during clearance. Plasma membrane-derived blebs contain nuclear chromatin (DNA and histones) but not components of the nuclear envelope. Existence of two immunologically distinct types of apoptotic blebs may provide new insights into clearance-related diseases.

Bilyy, Rostyslav O.; Shkandina, Tanya; Tomin, Andriy; Munoz, Luis E.; Franz, Sandra; Antonyuk, Volodymyr; Kit, Yuriy Ya.; Zirngibl, Matthias; Furnrohr, Barbara G.; Janko, Christina; Lauber, Kirsten; Schiller, Martin; Schett, Georg; Stoika, Rostyslav S.; Herrmann, Martin

2012-01-01

362

Activation of peritoneal macrophages to cytoxicity against B16 melanoma cells by Serratia marcescens polyribosome fractions  

SciTech Connect

Serratia marcescens polyribosomes (SMPR) have been shown to elicit an anti-tumor response in vivo. The in-vitro effects of SMPR on macrophages as the nonspecific mediators of the anti-tumor response have not previously been examined. The first objective of this research project is to corroborate and analyze the in-vivo results by the development and application of an in-vitro cytotoxicity assay. The second objective is to examine the effect of SMPR upon previously unstimulated peritoneal macrophages as representing the mechanism of cytotoxicity. The third objective is to identify the minimal effective component of SMPR responsible for an effect on macrophages. Results revealed that SMPR preparations exert a number of effects upon macrophages. Morphologic changes included increased spreading and increased perinuclear vacuolization. Macrophages were shown to be metabolically activate by two lines of evidence. SMPR-treated macrophages exhibited increased cellular metabolism by the increased uptake of /sup 3/H-thymidine and by the increased levels of secreted leucine aminopeptidase as compared to control macrophages. Results also showed that SMPR activates macrophages to cytotoxicity against syngeneic tumor target cells. Buoyant-density fractions were isolated and assayed for macrophage activating ability. Results showed 50S ribosomal subunits to be the smallest fraction effective for macrophage activation. Both the RNA and protein were necessary for complete effectiveness.

Hoover, S.K.

1985-01-01

363

Plant extract reduces tobacco smoke harmful effects on alveolar macrophage immune responses  

Microsoft Academic Search

Tobacco smoke is a major factor responsible for lung cancer and chronic obstructive pulmonary disease. Although the best solution to reduce the incidence of these diseases is to quit smoking, there are still a large number of smokers. Thus, given the immunoregulatory properties of plant extracts, their capacity to reduce tobacco smoke harmful effects on alveolar macrophage (AM) functions was

Elyse Y. Bissonnette; Léa-Isabelle Proulx; Annie Spahr; Marie France Janelle; Stéphane Dupuis

2006-01-01

364

The role of macrophage migration inhibitory factor in the inflammatory immune response and rheumatoid arthritis  

Microsoft Academic Search

Summary  Rheumatoid arthritis (RA) is a debilitating disease of unknown etiology. Although the pathogenesis of RA is multifactorial, the contribution of cytokines is undoubtedly pivotal in the progression of the inflammatory process. One cytokine gaining recognition for its importance in inflammation is macrophage migration inhibitory factor (MIF). Initially described as a biological activity, a broad range of functions of MIF has

Leilani L. Santos; Eric F. Morand

2006-01-01

365

Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes, independent of T-cell immunity.  

PubMed

Homologous and heterologous parenteral prime-mucosal boost immunizations have shown great promise in combating mucosal infections such as tuberculosis and AIDS. However, their immune mechanisms remain poorly defined. In particular, it is still unclear whether T-cell and innate immunity may be independently affected by these immunization modalities and how it impacts immune protective outcome. Using two virus-based tuberculosis vaccines (adenovirus (Ad) and vesicular stomatitis virus (VSV) vectors), we found that while both homologous (Ad/Ad) and heterologous (Ad/VSV) respiratory mucosal boost immunizations elicited similar T-cell responses in the lung, they led to drastically different immune protective outcomes. Compared with Ad-based boosting, VSV-based boosting resulted in poorly enhanced protection against tuberculosis. Such inferior protection was associated with differentially imprinted innate phagocytes, particularly the CD11c(+)CD11b(+/-) cells, in the lung. We identified heightened type 1 interferon (IFN) responses to be the triggering mechanism. Thus, increased IFN-? severely blunted interleukin-12 responses in infected phagocytes, which in turn impaired their nitric oxide production and antimycobacterial activities. Our study reveals that vaccine vectors may differentially imprint innate cells at the mucosal site of immunization, which can impact immune-protective outcome, independent of T-cell immunity, and it is of importance to determine both T-cell and innate cell immunity in vaccine studies. PMID:23131783

Jeyanathan, M; Damjanovic, D; Shaler, C R; Lai, R; Wortzman, M; Yin, C; Zganiacz, A; Lichty, B D; Xing, Z

2012-11-07

366

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

PubMed

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