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  1. Blockade of Mast Cell Activation Reduces Cutaneous Scar Formation

    PubMed Central

    Ranzer, Matthew J.; Wilgus, Traci A.; DiPietro, Luisa A.

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound. PMID:24465509

  2. Blockade of mast cell activation reduces cutaneous scar formation.

    PubMed

    Chen, Lin; Schrementi, Megan E; Ranzer, Matthew J; Wilgus, Traci A; DiPietro, Luisa A

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound. PMID:24465509

  3. Deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice

    PubMed Central

    Liu, Jian; Divoux, Adeline; Sun, Jiusong; Zhang, Jie; Clément, Karine; Glickman, Jonathan N.; Sukhova, Galina K.; Wolters, Paul J.; Du, Juan; Gorgun, Cem Z.; Doria, Alessandro; Libby, Peter; Blumberg, Richard S.; Kahn, Barbara B.; Hotamisligil, Gokhan S.; Shi, Guo-Ping

    2009-01-01

    Although mast cell functions classically relate to allergic responses1–3, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm, and cancer4–8. This study presents evidence that mast cells contribute importantly to diet-induced obesity and diabetes. White adipose tissues (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Genetically determined mast cell deficiency and pharmacological stabilization of mast cells in mice reduce body weight gain and levels of inflammatory cytokines, chemokines, and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer of cytokine-deficient mast cells established that these cells contribute to mice adipose tissue cysteine protease cathepsin expression, apoptosis, and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance by production of IL6 and IFN-γ. Mast cell stabilizing agents in clinical use reduced obesity and diabetes in mice, suggesting the potential of developing novel therapies for these common human metabolic disorders. PMID:19633655

  4. Mast cells and inflammation.

    PubMed

    Theoharides, Theoharis C; Alysandratos, Konstantinos-Dionysios; Angelidou, Asimenia; Delivanis, Danae-Anastasia; Sismanopoulos, Nikolaos; Zhang, Bodi; Asadi, Shahrzad; Vasiadi, Magdalini; Weng, Zuyi; Miniati, Alexandra; Kalogeromitros, Dimitrios

    2012-01-01

    Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation. PMID:21185371

  5. Mast cells and inflammation

    PubMed Central

    Theoharides, Theoharis C.; Alysandratos, Konstantinos-Dionysios; Angelidou, Asimenia; Delivanis, Danae-Anastasia; Sismanopoulos, Nikolaos; Zhang, Bodi; Asadi, Shahrzad; Vasiadi, Magdalini; Weng, Zuyi; Miniati, Alexandra; Kalogeromitros, Dimitrios

    2012-01-01

    Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. PMID:21185371

  6. Orf virus IL-10 reduces monocyte, dendritic cell and mast cell recruitment to inflamed skin.

    PubMed

    Bennett, Jared R; Lateef, Zabeen; Fleming, Stephen B; Mercer, Andrew A; Wise, Lyn M

    2016-02-01

    Orf virus (ORFV) is a zoonotic parapoxvirus that causes pustular dermatitis of sheep, and occasionally humans. Despite causing sustained infections, ORFV induces only a transient increase in pro-inflammatory signalling and the trafficking of innate immune cells within the skin seems to be impaired. An explanation for this tempered response to ORFV infection may lie in its expression of a homolog of the anti-inflammatory cytokine, interleukin (IL)-10. Using a murine model in which inflammation was induced by bacterial lipopolysaccharide, we examined the effects of the ORFV-IL-10 protein on immune cell trafficking to and from the skin. ORFV-IL-10 limited the recruitment of blood-derived Gr-1(int)/CD11b(int) monocytes, CD11c(+ve)/MHC-II(+ve) dendritic cells and c-kit(+ve)/FcεR1(+ve) mature mast cells into inflamed skin. ORFV-IL-10 also suppressed the activation of CD11c(+ve)/MHC-II(+ve) dendritic cells within the skin, reducing their trafficking to the draining lymph node. These findings suggest that expression of IL-10 by ORFV may contribute to the impaired trafficking of innate immune cells within infected skin. PMID:26732486

  7. Mast Cell Function

    PubMed Central

    da Silva, Elaine Zayas Marcelino; Jamur, Maria Célia

    2014-01-01

    Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role. PMID:25062998

  8. Mast cell stabilisers.

    PubMed

    Zhang, Tao; Finn, Deirdre Frances; Barlow, James William; Walsh, John Jarlath

    2016-05-01

    Mast cells play a critical role in type 1 hypersensitivity reactions. Indeed, mast cell mediators are implicated in many different conditions including allergic rhinitis, conjunctivitis, asthma, psoriasis, mastocytosis and the progression of many different cancers. Thus, there is intense interest in the development of agents which prevent mast cell mediator release or which inhibit the actions of such mediators once released into the environment of the cell. Much progress into the design of new agents has been made since the initial discovery of the mast cell stabilising properties of khellin from Ammi visnaga and the clinical approval of cromolyn sodium. This review critically examines the progress that has been made in the intervening years from the design of new agents that target a specific signalling event in the mast cell degranulation pathway to those agents which have been developed where the precise mechanism of action remains elusive. Particular emphasis is also placed on clinically used drugs for other indications that stabilise mast cells and how this additional action may be harnessed for their clinical use in disease processes where mast cells are implicated. PMID:26130122

  9. Cinnamon extract reduces symptoms, inflammatory mediators and mast cell markers in murine IL-10(-/-) colitis.

    PubMed

    Hagenlocher, Yvonne; Hösel, Angela; Bischoff, Stephan C; Lorentz, Axel

    2016-04-01

    Inflammatory bowel disease (IBD) shows an increasing prevalence and harm in western countries. Conventional therapies are associated with bad compliance and adverse side effects. Natural substances like cinnamon extract (CE) could be an additional therapy. We found recently that CE acts anti-inflammatory on mast cells - discussed of being relevant in IBD. Here, we analysed the effects of CE on murine IL-10(-/-) colitis as model for IBD. Mice were treated 12 weeks with or without CE in drinking water. Clinical scores and disease activity index were assessed. Colonic tissue samples were analysed for infiltration, tissue damage, bowel wall thickness, expression of pro-inflammatory mediators, mast cell proteases, tight junction proteins, and NF-κB signaling. Following treatment with CE, symptoms of murine colitis as well as increased infiltration of immune cells, tissue damage and bowel wall thickness in colon tissue of IL-10(-/-) mice were diminished significantly. MIP-2, TNF, IFNγ, CCL2, CCL3, CCL4 and IL-1β as well as MC-CPA, MCP-1 and MCP-4 were strongly upregulated in IL-10(-/-) mice compared to WT, but noteworthy not in CE group. Expression of tight junction proteins was not influenced by CE. Phosphorylation of IκB was slightly down-regulated in CE treated IL-10(-/-) mice compared to IL-10(-/-) controls. In summary, CE decreases inflammatory symptoms and expression of inflammatory markers in murine IL-10(-/-) colitis. CE has no influence on tight junction proteins, but seems acting via reducing pro-inflammatory mediators and recruitment of neutrophil granulocytes probably by inhibiting NF-κB signaling. PMID:27012624

  10. Mast cells and mastocytosis

    PubMed Central

    2008-01-01

    Mast cells have been recognized for well over 100 years. With time, human mast cells have been documented to originate from CD34+ cells, and have been implicated in host responses in both innate and acquired immunity. In clinical immunology, they are recognized for their central role in IgE-mediated degranulation and allergic inflammation by virtue of their expression of the high-affinity receptor for IgE and release of potent proinflammatory mediators. In hematology, the clinical disease of mastocytosis is characterized by a pathologic increase of mast cells in tissues, often associated with mutations in KIT, the receptor for stem cell factor. More recently, and with increased understanding of how human mast cells are activated through receptors including the high-affinity receptor for IgE and KIT, specific tyrosine kinase inhibitors have been identified with the potential to interrupt signaling pathways and thus limit the proliferation of mast cells as well as their activation through immunoglobulin receptors. PMID:18684881

  11. Mast Cells and Neuroinflammation

    PubMed Central

    Dong, Hongquan; Zhang, Xiang; Qian, Yanning

    2014-01-01

    It has been determined that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. There is an emerging realization that glia and microglia, in particular, (which are the brain’s resident macrophages), are an important source of inflammatory mediators and may have fundamental roles in CNS disorders. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin, such as mast cells. Mast cells reside in the CNS and are capable of migrating across the blood-brain barrier (BBB) in situations where the barrier is compromised as a result of CNS pathology. Mast cells are both sensors and effectors in communication among nervous, vascular, and immune systems. In the brain, they reside on the brain side of the BBB, and interact with astrocytes, microglia, and blood vessels via their neuroactive stored and newly synthesized chemicals. They are first responders, acting as catalysts and recruiters to initiate, amplify, and prolong other immune and nervous responses upon activation. Mast cells both promote deleterious outcomes in brain function and contribute to normative behavioral functioning, particularly cognition and emotion. Mast cells may play a key role in treating systemic inflammation or blockade of signaling pathways from the periphery to the brain. PMID:25529562

  12. Mast Cells and Anaphylaxis.

    PubMed

    Lieberman, Phil; Garvey, Lene Heise

    2016-03-01

    For half a century, it has been known that the mast cell is the cell responsible for the majority of anaphylactic events. Its mediators, taken as a whole, are capable of producing all of the clinical manifestations of these events. With the discovery of immunoglobulin E (IgE), it was originally felt that the vast majority of anaphylactic episodes were due to antigen coupling with two cell-bound IgE molecules. More recently it has been learned that many episodes are produced by direct activation of mast cells, not involving antigen binding to IgE, and that monomeric IgE under certain conditions can also cause degranulation. Of note--in regard to antigen independent degranulation--are recent reports that the human G-protein-coupled receptor, MRGPRX2, may be the receptor for many drugs and cationic proteins capable of producing direct mast cell degranulation and anaphylactic events. PMID:26857018

  13. Mast cells and metabolic syndrome

    PubMed Central

    Zhang, Jie; Shi, Guo-Ping

    2011-01-01

    Mast cells are critical effectors in the development of allergic diseases and in many immunoglobulin E–mediated immune responses. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell-specific chymase and tryptase. Like macrophages and T lymphocytes, mast cells are inflammatory cells, and they participate in the pathogenesis of inflammatory diseases such as cardiovascular complications and metabolic disorders. Recent observations suggested that mast cells are involved in insulin resistance and type 2 diabetes. Data from animal models proved the direct participation of mast cells in diet-induced obesity and diabetes. Although the mechanisms by which mast cells participate in these metabolic diseases are not fully understood, established mast cell pathobiology in cardiovascular diseases and effective mast cell inhibitor medications used in pre-formed obesity and diabetes in experimental models offer hope to patients with these common chronic inflammatory diseases. PMID:21185370

  14. Canine mast cell tumors.

    PubMed

    Macy, D W

    1985-07-01

    Despite the fact that the mast cell tumor is a common neoplasm of the dog, we still have only a meager understanding of its etiology and biologic behavior. Many of the published recommendations for treatment are based on opinion rather than facts derived from careful studies and should be viewed with some skepticism. Because of the infrequent occurrence of this tumor in man, only a limited amount of help can be expected from human oncologists; therefore, burden of responsibility for progress in predicting behavior and developing treatment effective for canine mast cell tumors must fall on the shoulders of the veterinary profession. PMID:3929444

  15. Mast Cell and Autoimmune Diseases

    PubMed Central

    Xu, Yunzhi; Chen, Guangjie

    2015-01-01

    Mast cells are important in innate immune system. They have been appreciated as potent contributors to allergic reaction. However, increasing evidence implicates the important role of mast cells in autoimmune disease like rheumatoid arthritis and multiple sclerosis. Here we review the current stage of knowledge about mast cells in autoimmune diseases. PMID:25944979

  16. Mast cells and COPD.

    PubMed

    Mortaz, Esmaeil; Folkerts, Gert; Redegeld, Frank

    2011-08-01

    The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells. The relative contribution of mast cells to airway injury and remodeling is not well documented. In this review, an overview is given on the possible role of mast cells and their mediators in the pathogenesis of COPD. Activation of mast cells and mast cell signaling in response to exposure to cigarette smoke is further discussed. PMID:21463700

  17. The Importance of Mast Cells in Dermal Scarring

    PubMed Central

    Wilgus, Traci A.; Wulff, Brian C.

    2014-01-01

    Significance: Mast cells are resident inflammatory cells present in high numbers in the skin. They are one of the first cell types to respond to damage and they do so by quickly releasing a variety of preformed mediators that are stored within mast cell granules. Mast cells are not only active early on, where they help induce inflammation, but they also stimulate the proliferation of several important cell types and influence the production and remodeling of collagen. Recent Advances: Recent studies have highlighted the importance of mast cells in determining the amount of scar tissue that forms as a result of the repair process. Mast cells are found in low numbers and in a less activated state in scarless wounds, whereas high numbers of activated mast cells are associated with scarring and fibrosis. Furthermore, animals that lack mast cells or have been treated with degranulation inhibitors or drugs that block the activity of mast cell proteases have been shown to heal with reduced scar tissue. Critical Issues: Despite evidence suggesting that mast cells regulate scar tissue development, the entire range of mast cell activities during wound repair and scar formation has not been completely characterized. In addition, the potential therapeutic benefits of targeting mast cells clinically have yet to be fully explored. Future Directions: More studies are needed to determine whether inhibiting mast cell activation and blocking the function of mast cell mediators are viable options to prevent or reduce the appearance of scars. PMID:24757590

  18. The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures

    PubMed Central

    Hart, David A.; Befus, A. Dean; Salo, Paul T.; Zhang, Mei; Hildebrand, Kevin A.

    2013-01-01

    Objectives Using a rabbit model of post-traumatic joint contractures, we investigated whether treatment with a mast cell stabilizer after joint injury would lessen the molecular manifestations of joint capsule fibrosis. Methods Surgical joint injury was used to create stable post-traumatic contractures of the knee in skeletally mature New Zealand white rabbits. Four groups of animals were studied: a non-operated control group (n = 8), an operated contracture group (n = 13) and two operated groups treated with the mast cell stabilizer, ketotifen, at doses of 0.5 mg/kg (n = 9) and 1.0 mg/kg (n = 9) twice daily. Joint capsule fibrosis was assessed by quantifying the mRNA and protein levels of α-SMA, tryptase, TGF-β1, collagen I and collagen III. Significance was tested using an ANOVA analysis of variance. Results The protein and mRNA levels of α-SMA, TGF-β1, tryptase and collagen I and III were significantly elevated in the operated contracture group compared to control (p < 0.01). In both ketotifen-treated groups, protein and mRNA levels of α-SMA, TGF-β1 and collagen I were significantly reduced compared to the operated contracture group (p < 0.01). Conclusions These data suggest an inflammatory pathway mediated by mast cell activation is involved in joint capsule fibrosis after traumatic injury. PMID:22173279

  19. Mast cells in rheumatic disease.

    PubMed

    Suurmond, Jolien; van der Velden, Daniël; Kuiper, Johan; Bot, Ilze; Toes, René E M

    2016-05-01

    Rheumatoid Arthritis is a chronic autoimmune disease with a complex disease pathogenesis leading to inflammation and destruction of synovial tissue in the joint. Several molecules lead to activation of immune pathways, including autoantibodies, Toll-Like Receptor ligands and cytokines. These pathways can cooperate to create the pro-inflammatory environment that results in tissue destruction. Each of these pathways can activate mast cells, inducing the release of a variety of inflammatory mediators, and in combination can markedly enhance mast cell responses. Mast cell-derived cytokines, chemokines, and proteases have the potential to induce recruitment of other leukocytes able to evoke tissue remodeling or destruction. Likewise, mast cells can secrete a plethora of factors that can contribute to tissue remodeling and fibroblast activation. Although the functional role of mast cells in arthritis pathogenesis in mice is not yet elucidated, the increased numbers of mast cells and mast cell-specific mediators in synovial tissue of rheumatoid arthritis patients suggest that mast cell activation in rheumatoid arthritis may contribute to its pathogenesis. PMID:25943290

  20. Perivascular mast cells regulate vein graft neointimal formation and remodeling

    PubMed Central

    Grassia, Gianluca; Cambrook, Helen; Ialenti, Armando; MacRitchie, Neil; Carberry, Jaclyn; Lawrence, Catherine

    2015-01-01

    Objective. Emerging evidence suggests an important role for mast cells in vein graft failure. This study addressed the hypothesis that perivascular mast cells regulate in situ vascular inflammatory and proliferative responses and subsequent vein graft neointimal lesion formation, using an optimized local mast cell reconstitution method. Methods and Results. Neointimal hyperplasia was induced by insertion of a vein graft into the right carotid artery in wild type and mast cell deficient KitW−sh/W−sh mice. In some experiments, mast cells were reconstituted systemically (tail vein injection of bone marrow-derived mast cells) or locally (directly into the right neck area) prior to vein grafting. Vein graft neointimal lesion formation was significantly (P < 0.05) reduced in KitW−sh/W−sh mice. Mast cell deficiency reduced the number of proliferating cells, and inhibited L-selectin, CCL2, M-CSF and MIP-3α expression in the vein grafts. Local but not systemic mast cell reconstitution restored a perivascular mast cell population that subsequently promoted neointimal formation in mast cell deficient mice. Conclusion. Our data demonstrate that perivascular mast cells play a key role in promoting neointima formation by inducing local acute inflammatory and proliferative responses. These results suggest that ex vivo intraoperative targeting of mast cells may have therapeutic potential for the prevention of pathological vein graft remodeling. PMID:26312183

  1. Mast cells in gastrointestinal disorders.

    PubMed

    Bischoff, Stephan C

    2016-05-01

    Mast cells are constitutively found in the gastrointestinal (GI) tract. The three major physiological functions of GI mast cells comprise of - as far as we know - regulation of GI functions, namely epithelial and endothelial functions, crosstalk with the enteric nervous system, and contribution to the host defense against bacterial, viral and parasitic agents. A number of chronic GI diseases, including inflammatory bowel disease (Crohn's disease, ulcerative colitis), celiac disease, irritable bowel syndrome, and food allergies, are thought to be associated with mast cell hyperplasia and humoral activity. Clinical conditions characterized by a decrease in mast cell functionality are not known so far. In the present review, we summarize current evidence which show that human mast cells play a central role at the GI barrier, both in health and disease. PMID:26852959

  2. Mast cells enhance T cell activation: Importance of mast cell-derived TNF

    NASA Astrophysics Data System (ADS)

    Nakae, Susumu; Suto, Hajime; Kakurai, Maki; Sedgwick, Jonathon D.; Tsai, Mindy; Galli, Stephen J.

    2005-05-01

    Mast cells are not only important effector cells in immediate hypersensitivity reactions and immune responses to pathogens but also can contribute to T cell-mediated disorders. However, the mechanisms by which mast cells might influence T cells in such settings are not fully understood. We find that mast cells can enhance proliferation and cytokine production in multiple T cell subsets. Mast cell-dependent enhancement of T cell activation can be promoted by FcRI-dependent mast cell activation, TNF production by both mast cells and T cells, and mast cell-T cell contact. However, at high concentrations of cells, mast cells can promote T cell activation independent of IgE or TNF. Finally, mast cells also can promote T cell activation by means of soluble factors. These findings identify multiple mechanisms by which mast cells can influence T cell proliferation and cytokine production. allergy | asthma | autoimmunity | cytokines | immune response

  3. Mast cells in laser and surgical wounds.

    PubMed

    Pinheiro, A L; Browne, R M; Frame, J W; Matthews, J B

    1995-01-01

    Precooling of tissues was investigated as a possible means of reducing thermal damage during CO2 laser surgery of the oral mucosa. The changes in mast cells in scalpel, and in non-cooled and precooled (tissue temperature lowered to approximately 10 degrees C) CO2 laser wounds were studied. Standard wounds five mm in length were created with the CO2 laser or scalpel on the dorsum of the tongues of 32 Sprague-Dawley rats under general anesthesia with fentanyl/fluanisone and midazolam. Animals were killed with excess anesthetic immediately or six hours after surgery, their tongues were removed, trimmed, fixed in neutral formalin and processed to paraffin wax. Acid (pH 1.4) toluidine blue stained sections were used to count normal and degranulated mast cells in five fields (0.1 mm2) located at defined positions immediately adjacent to the wound site. At both 0 and 6 hours normal mast cell numbers were significantly different between treatment groups (P<0.045; ANOVA) with mean numbers highest in scalpel wounds and lowest in uncooled laser wounds. Similarly, at 0 time, there were significant differences in degranulated mast cells between treatment groups (P=0.004; ANOVA) but highest numbers were detected in uncooled laser wounds and lowest in scalpel wounds. There were no significant differences in degranulated mast cell counts at six hours although there was a similar distribution in numbers between groups. Total numbers of mast cells (normal + degranulated) did not differ between treatment groups. These results demonstrated that i) laser wounds are associated with greater levels of mast cell degranulation than scalpel wounds and ii) precooling of tissues prior to laser treatment decreases the level of mast cell degranulation. It is concluded that tissue damage in CO2 laser surgery may be reduced by precooling of tissue. PMID:8688643

  4. Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis.

    PubMed

    Gan, Poh-Yi; Summers, Shaun A; Ooi, Joshua D; O'Sullivan, Kim M; Tan, Diana S Y; Muljadi, Ruth C M; Odobasic, Dragana; Kitching, A Richard; Holdsworth, Stephen R

    2012-12-01

    Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis. PMID:23138486

  5. Cytoskeleton in Mast Cell Signaling

    PubMed Central

    Dráber, Pavel; Sulimenko, Vadym; Dráberová, Eduarda

    2012-01-01

    Mast cell activation mediated by the high affinity receptor for IgE (FcεRI) is a key event in allergic response and inflammation. Other receptors on mast cells, as c-Kit for stem cell factor and G protein-coupled receptors (GPCRs) synergistically enhance the FcεRI-mediated release of inflammatory mediators. Activation of various signaling pathways in mast cells results in changes in cell morphology, adhesion to substrate, exocytosis, and migration. Reorganization of cytoskeleton is pivotal in all these processes. Cytoskeletal proteins also play an important role in initial stages of FcεRI and other surface receptors induced triggering. Highly dynamic microtubules formed by αβ-tubulin dimers as well as microfilaments build up from polymerized actin are affected in activated cells by kinases/phosphatases, Rho GTPases and changes in concentration of cytosolic Ca2+. Also important are nucleation proteins; the γ-tubulin complexes in case of microtubules or Arp 2/3 complex with its nucleation promoting factors and formins in case of microfilaments. The dynamic nature of microtubules and microfilaments in activated cells depends on many associated/regulatory proteins. Changes in rigidity of activated mast cells reflect changes in intermediate filaments build up from vimentin. This review offers a critical appraisal of current knowledge on the role of cytoskeleton in mast cells signaling. PMID:22654883

  6. Mast Cells Can Enhance Resistance to Snake and Honeybee Venoms

    NASA Astrophysics Data System (ADS)

    Metz, Martin; Piliponsky, Adrian M.; Chen, Ching-Cheng; Lammel, Verena; Åbrink, Magnus; Pejler, Gunnar; Tsai, Mindy; Galli, Stephen J.

    2006-07-01

    Snake or honeybee envenomation can cause substantial morbidity and mortality, and it has been proposed that the activation of mast cells by snake or insect venoms can contribute to these effects. We show, in contrast, that mast cells can significantly reduce snake-venom-induced pathology in mice, at least in part by releasing carboxypeptidase A and possibly other proteases, which can degrade venom components. Mast cells also significantly reduced the morbidity and mortality induced by honeybee venom. These findings identify a new biological function for mast cells in enhancing resistance to the morbidity and mortality induced by animal venoms.

  7. Mast cells in mammalian brain.

    PubMed

    Dropp, J J

    1976-01-01

    Mast cells, which had until recently been believed to be not present in the mammalian brain, were studied in the brains of 29 mammalian species. Although there was considerable intraspecific and interspecific variation, mast cells were most numerous within the leptomeninges (especially in those overlying the cerebrum and the dorsal thalamus - most rodents, most carnivores, chimpanzees, squirrel monkeys and elephant), the cerebral cortex (most rodents, tiger, fox, chimpanzee, tarsier, and elephant) and in many nuclei of the dorsal thalamus (most rodents, tiger, lion, and fox). In some mammals, mast cells were also numerous in the stroma of the telencephalic choroid plexuses (chimpanzee, squirrel monkey), the putamen and the claustrum (chimpanzee), the subfornical organ (pack rat, tiger, chimpanzee), the olfactory peduncles (hooded rat, albino rat), the stroma of the diencephalic choroid plexus (lion, chimpanzee, squirrel monkey), the pineal organ (chimpanzee, squirrel monkey), some nuclei of the hypothalamus (tiger), the infundibulum (hooded rat, tiger, fox) the area postrema (pack rat, chinchilla, lion, spider monkey, chimpanzee, fox) and some nuclei and tracts of the metencephalon and the myelencephalon (tiger). Neither the sex of the animal nor electrolytic lesions made in the brains of some of the animals at various times prior to sacrifice appeared to effect the number and the distribution of mast cells. Age-related changes in mast cell number and distribution were detected in the albino rat. PMID:961335

  8. Augmentation of reverse arthus reaction by mast cells in mice.

    PubMed Central

    Zhang, Y; Ramos, B F; Jakschik, B A

    1991-01-01

    Immune complex-induced injury is an important pathogenic factor in antibody-mediated nephritis, systemic lupus erythematosus, rheumatoid arthritis, and other diseases. In this study we investigated the role mast cells in immune complex-mediated injury in mouse skin. Reverse Arthus reaction was induced in mast cell-deficient WBB6F1-W/Wv mice and their congenic controls (WBB6F1(-)+/+). Serial skin sections were evaluated for neutrophil infiltration, edema, and hemorrhage. In WBB6F1-W/Wv mice the neutrophil influx was only 40% and edema 60% of that in congenic controls. Hemorrhage was also significantly reduced in the mast cell-deficient mice. After mast cell reconstitution, the magnitude of the reaction in WBB6F1-W/Wv was equivalent to that in WBB6F1(-)+/+ mice. Mast cell release in reverse Arthus reaction was evaluated by measuring fluorescence intensity after avidin-FITC staining of mast cell granules. There was a 70% decrease in fluorescence intensity. The 5-lipoxygenase inhibitor A-63162 significantly decreased neutrophil accumulation (40%), edema (60%), and hemorrhage in WBB6F1(-)+/+, but not in mast cell-deficient mice. Mast cell reconstitution of WBB6F1-W/Wv mice restored the effect of A-63162. The results indicate that mast cells and their mediators, including leukotrienes, make an important contribution to reverse Arthus reaction. Images PMID:1832174

  9. Mast cell secretory granules: armed for battle.

    PubMed

    Wernersson, Sara; Pejler, Gunnar

    2014-07-01

    Mast cells are important effector cells of the immune system and recent studies show that they have immunomodulatory roles in diverse processes in both health and disease. Mast cells are distinguished by their high content of electron-dense secretory granules, which are filled with large amounts of preformed and pre-activated immunomodulatory compounds. When appropriately activated, mast cells undergo degranulation, a process by which these preformed granule compounds are rapidly released into the surroundings. In many cases, the effects that mast cells have on an immune response are closely associated with the biological actions of the granule compounds that they release, as exemplified by the recent studies showing that mast cell granule proteases account for many of the protective and detrimental effects of mast cells in various inflammatory settings. In this Review, we discuss the current knowledge of mast cell secretory granules. PMID:24903914

  10. Lipid Rafts in Mast Cell Biology

    PubMed Central

    Silveira e Souza, Adriana Maria Mariano; Mazucato, Vivian Marino; Jamur, Maria Célia; Oliver, Constance

    2011-01-01

    Mast cells have long been recognized to have a direct and critical role in allergic and inflammatory reactions. In allergic diseases, these cells exert both local and systemic responses, including allergic rhinitis and anaphylaxis. Mast cell mediators are also related to many chronic inflammatory conditions. Besides the roles in pathological conditions, the biological functions of mast cells include roles in innate immunity, involvement in host defense mechanisms against parasites, immunomodulation of the immune system, tissue repair, and angiogenesis. Despite their growing significance in physiological and pathological conditions, much still remains to be learned about mast cell biology. This paper presents evidence that lipid rafts or raft components modulate many of the biological processes in mast cells, such as degranulation and endocytosis, play a role in mast cell development and recruitment, and contribute to the overall preservation of mast cell structure and organization. PMID:21490812

  11. Mast Cells in Allergic Diseases and Mastocytosis

    PubMed Central

    Marquardt, Diana L.; Wasserman, Stephen I.

    1982-01-01

    Mast cells with their stores of vasoactive and chemotactic mediators are central to the pathogenesis of allergic diseases. The cross-linking of receptorbound IgE molecules on the surface of mast cells initiates a complex chain of events, including calcium ion influx, phospholipid methylation and turnover and cyclic nucleotide metabolism, ultimately resulting in the release of mediators of immediate hypersensitivity. These mast cell mediators are important in smooth muscle reactivity, in the recruitment of eosinophilic and neutrophilic leukocytes and in the generation of secondary chemical mediators. Histologic evidence of mast cell degranulation, biochemical evidence of mast cell mediators in blood and tissues and clinical evidence of signs and symptoms reproducible by these mediators have strongly supported the crucial role of mast cells in asthma, urticaria, anaphylaxis, rhinitis and mastocytosis. Because of their unique location at host environment interfaces, mast cells may both participate in allergic diseases and promote homeostasis. ImagesFigure 1.Figure 2.Figure 3. PMID:6293204

  12. Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis: role of mast cells.

    PubMed

    Iuvone, Teresa; Affaitati, Giannapia; De Filippis, Daniele; Lopopolo, Mariangela; Grassia, Gianluca; Lapenna, Domenico; Negro, Luana; Costantini, Raffaele; Vaia, Massimo; Cipollone, Francesco; Ialenti, Armando; Giamberardino, Maria Adele

    2016-01-01

    The effects of ultramicronized palmitoylethanolamide were evaluated on pain behaviours and markers of mast cell (MC) activity in a rat model of endometriosis plus ureteral calculosis (ENDO+STONE)-induced viscerovisceral hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of endometriosis were randomly assigned to receive active (ultramicronized palmitoylethanolamide 10 mg·kg(-1)·d(-1), orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels, chymase, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and Flk-1 (VEGF receptor) in cysts, and NGF in dorsal root ganglia (DRG). Ultramicronized palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine pain, and smaller cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P < 0.01), vessel number (P < 0.01), chymase (P < 0.05), NGF (P < 0.05), VEGF (P < 0.01), and Flk-1 (P < 0.01) expression in cysts and NGF expression in DRG (P < 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with cyst diameter, MC number and chymase in cysts, and NGF in cysts and DRG (0.02 < P < 0.0002). Ultramicronized palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics. PMID:25974242

  13. Anti-CD40 Ab- or 8-oxo-dG-enhanced Treg cells reduce development of experimental autoimmune encephalomyelitis via down-regulating migration and activation of mast cells.

    PubMed

    Hong, Gwan Ui; Kim, Nam Goo; Jeoung, Dooil; Ro, Jai Youl

    2013-07-15

    This study investigated whether anti-CD40 Ab and 8-oxo-dG attenuate mast cell migration and EAE development. Anti-CD40 Ab and 8-oxo-dG reduced EAE scores, mast cell numbers, expression of adhesion molecules, OX40L and Act1, levels of TNF-α, LTs, expression of cytokines, and co-localization of Treg cells and mast cells, all of which are increased in EAE-brain tissues. Each treatment enhanced Treg cells, expression of OX40, and cytokines related to suppressive function of Treg cells in EAE brain tissues. Act-BMMCs with Treg cells reduced expression of OX40L and CCL2/CCR2, VCAM-1, PECAM-1, [Ca²⁺]i levels, release of mediators, various signaling molecules, Act1 related to IL-17a signals versus those in act-BMMCs without Treg cells. The data suggest that IL-10- and IL-35-producing Foxp3⁺-Treg cells, enhanced by anti-CD40 Ab or 8-oxo-dG, suppress migration of mast cells through down-regulating the expression of adhesion molecules, and suppress mast cell activation through cell-to-cell cross-talk via OX40/OX40L in EAE development. PMID:23622820

  14. Genitourinary mast cells and survival.

    PubMed

    Theoharides, Theoharis C; Stewart, Julia M

    2015-10-01

    Mast cells (MCs) are ubiquitous in the body, but they have historically been associated with allergies, and most recently with regulation of immunity and inflammation. However, it remains a puzzle why so many MCs are located in the diencephalon, which regulates emotions and in the genitourinary tract, including the bladder, prostate, penis, vagina and uterus that hardly ever get allergic reactions. A number of papers have reported that MCs have estrogen, gonadotropin and corticotropin-releasing hormone (CRH) receptors. Moreover, animal experiments have shown that diencephalic MCs increase in number during courting in doves. We had reported that allergic stimulation of nasal MCs leads to hypothalamic-pituitary adrenal (HPA) activation. Interestingly, anecdotal information indicates that female patients with mastocytosis or mast cell activation syndrome may have increased libido. Preliminary evidence also suggests that MCs may have olfactory receptors. MCs may, therefore, have been retained phylogenetically not only to "smell danger", but to promote survival and procreation. PMID:26813805

  15. Genitourinary mast cells and survival

    PubMed Central

    Stewart, Julia M.

    2015-01-01

    Mast cells (MCs) are ubiquitous in the body, but they have historically been associated with allergies, and most recently with regulation of immunity and inflammation. However, it remains a puzzle why so many MCs are located in the diencephalon, which regulates emotions and in the genitourinary tract, including the bladder, prostate, penis, vagina and uterus that hardly ever get allergic reactions. A number of papers have reported that MCs have estrogen, gonadotropin and corticotropin-releasing hormone (CRH) receptors. Moreover, animal experiments have shown that diencephalic MCs increase in number during courting in doves. We had reported that allergic stimulation of nasal MCs leads to hypothalamic-pituitary adrenal (HPA) activation. Interestingly, anecdotal information indicates that female patients with mastocytosis or mast cell activation syndrome may have increased libido. Preliminary evidence also suggests that MCs may have olfactory receptors. MCs may, therefore, have been retained phylogenetically not only to “smell danger”, but to promote survival and procreation. PMID:26813805

  16. Mast cell stabilization: novel medication for obesity and diabetes

    PubMed Central

    Wang, Jing; Shi, Guo-Ping

    2012-01-01

    Summary Mast cells are essential in allergic responses and beyond. White adipose tissue from obese humans contains large numbers of mast cells. Serum mast cell tryptase levels are also significantly higher in obese subjects than in lean subjects, suggesting a role of these inflammatory cells in obesity and diabetes. Two types of mast cell-deficient mice, along with corresponding wild-type control mice, were fed a Western diet to induce obesity and diabetes. We also used two anti-allergy drugs, cromolyn and ketotifen (Zaditor), to treat wild-type mice during intake of a Western diet or after the onset of obesity and diabetes, to examine the possible prevention or reversal of these conditions. Mast cell deficiency or pharmacological stabilization reduced body weight gain and improved glucose and insulin sensitivities. These common, side effect-free drugs also reduced pre-established obesity and diabetes without noticeable toxicity. Mechanistic studies suggest that mast cells participate in these metabolic disorders by affecting energy expenditure, protease expression, angiogenesis, apoptosis, and preadipocyte differentiation. These observations open a new era of basic research regarding mast cells, and offer hope to patients suffering from these metabolic disorders. PMID:22069285

  17. The role of mast cells in cancers

    PubMed Central

    Maciel, Thiago T.; Moura, Ivan C.

    2015-01-01

    Mast cells are immune cells that accumulate in the tumors and their microenvironment during disease progression. Mast cells are armed with a wide array of receptors that sense environment modifications and, upon stimulation, they are able to secrete several biologically active factors involved in the modulation of tumor growth. For example, mast cells are able to secrete pro-angiogenic and growth factors but also pro- and anti-inflammatory mediators. Recent studies have allowed substantial progress in understanding the role of mast cells in tumorigenesis/disease progression but further studies are necessary to completely elucidate their impact in the pathophysiology of cancer. Here we review observations suggesting that mast cells could modulate tumor growth in humans. We also discuss the drawbacks related to observations from mast cell-deficient mouse models, which could have consequences in the determination of a potential causative relationship between mast cells and cancer. We believe that the understanding of the precise role of mast cells in tumor development and progression will be of critical importance for the development of new targeted therapies in human cancers. PMID:25705392

  18. Mast cells, angiogenesis and cancer.

    PubMed

    Ribatti, Domenico; Crivellato, Enrico

    2011-01-01

    Mast cells (MCs) were first described by Paul Ehrlich 1 in his doctoral thesis. MCs have long been implicated in the pathogenesis of allergic reactions and certain protective responses to parasites. As most tumors contain inflammatory cell infiltrates, which often include plentiful MCs, the question as to the possible contribution of MCs to tumor development has progressively been emerging. In this chapter, the specific involvement of MCs in tumor biology and tumor fate will be considered, with particular emphasis on the capacity of these cells to stimulate tumor growth by promoting angiogenesis and lymphangiogenesis. Data from experimental carcinogenesis and from different tumor settings in human pathology will be summarized. Information to be presented will suggest that MCs may serve as a novel therapeutic target for cancer treatment. PMID:21713661

  19. Mast Cells Contribute to Porphyromonas gingivalis-induced Bone Loss.

    PubMed

    Malcolm, J; Millington, O; Millhouse, E; Campbell, L; Adrados Planell, A; Butcher, J P; Lawrence, C; Ross, K; Ramage, G; McInnes, I B; Culshaw, S

    2016-06-01

    Periodontitis is a chronic inflammatory and bone-destructive disease. Development of periodontitis is associated with dysbiosis of the microbial community, which may be caused by periodontal bacteria, such as Porphyromonas gingivalis Mast cells are sentinels at mucosal surfaces and are a potent source of inflammatory mediators, including tumor necrosis factors (TNF), although their role in the pathogenesis of periodontitis remains to be elucidated. This study sought to determine the contribution of mast cells to local bone destruction following oral infection with P. gingivalis Mast cell-deficient mice (Kit(W-sh/W-sh)) were protected from P. gingivalis-induced alveolar bone loss, with a reduction in anti-P. gingivalis serum antibody titers compared with wild-type infected controls. Furthermore, mast cell-deficient mice had reduced expression of Tnf, Il6, and Il1b mRNA in gingival tissues compared with wild-type mice. Mast cell-engrafted Kit(W-sh/W-sh) mice infected with P. gingivalis demonstrated alveolar bone loss and serum anti-P. gingivalis antibody titers equivalent to wild-type infected mice. The expression of Tnf mRNA in gingival tissues of Kit(W-sh/W-sh) mice was elevated following the engraftment of mast cells, indicating that mast cells contributed to the Tnf transcript in gingival tissues. In vitro, mast cells degranulated and released significant TNF in response to oral bacteria, and neutralizing TNF in vivo abrogated alveolar bone loss following P. gingivalis infection. These data indicate that mast cells and TNF contribute to the immunopathogenesis of periodontitis and may offer therapeutic targets. PMID:26933137

  20. The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

    PubMed Central

    Wang, Leo D.; Rao, Tata Nageswara; Rowe, R. Grant; Nguyen, Phi T.; Sullivan, Jessica L.; Pearson, Daniel S.; Doulatov, Sergei; Wu, Linwei; Lindsley, R. Coleman; Zhu, Hao; DeAngelo, Daniel J.; Daley, George Q.; Wagers, Amy J.

    2015-01-01

    Mast cells are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration, and tumor progression. Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused mast cell accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhanced mast cell specification. In addition, LIN28B-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28B in abnormal mast cells from patients with systemic mastocytosis (SM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease. PMID:25655194

  1. Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells.

    PubMed

    Stoyanov, Evgeniy; Uddin, Mohib; Mankuta, David; Dubinett, Steven M; Levi-Schaffer, Francesca

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with an extremely low survival rate. It is characterized by a chronic inflammatory process with intense mast cell infiltrate that is associated with reduced survival. The aim of this study was to test the hypothesis that mast cells have an enhancing effect on NSCLC proliferation. To assess the tumor-promoting potential of mast cells, we used the human alveolar basal adenocarcinoma (A549) and the mouse Lewis lung carcinoma (LLC) cell lines, umbilical cord blood-derived mast cells (CBMC) and the mast cell-deficient mouse Sash model. The proliferation rate of A549/LLC cells was markedly increased by mast cells and histamine. Histamine proliferating activity was mediated via H(1), H(2) and H(4) receptors and caused ERK phosphorylation. LLC induced in Sash mice or in wild-type mice treated with the mast cell stabilizer nedocromil sodium displayed an accelerated growth (number of metastic colonies in the lungs, total lung area and lung/total mice weight ratio). In summary, we have shown a significant effect of mast cells and histamine in enhancing NSCLC/LLCX growth in vitro, while in a mouse LLC model in vivo we have found that mast cells are important negative regulators of cancer development. Therefore our results would indicate a pro-tumorogenic effect of the mast cells in vitro on established lung tumor cell lines, and anti-tumorogenic effect in mice at lung cancer induction. In conclusion, mast cell/anti-histamine targeted therapies should carefully consider this dual effect. PMID:21733595

  2. Carbonic anhydrase enzymes regulate mast cell-mediated inflammation.

    PubMed

    Henry, Everett K; Sy, Chandler B; Inclan-Rico, Juan M; Espinosa, Vanessa; Ghanny, Saleena S; Dwyer, Daniel F; Soteropoulos, Patricia; Rivera, Amariliz; Siracusa, Mark C

    2016-08-22

    Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. In this study, we show that carbonic anhydrase (Car) enzymes are up-regulated in type 2-associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent mouse mast cell responses and inflammation after Trichinella spiralis infection or the induction of food allergy-like disease. Further, we used CRISPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively, these experiments identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be used to treat mast cell-mediated inflammation. PMID:27526715

  3. Mast Cell: A Multi-Functional Master Cell

    PubMed Central

    Krystel-Whittemore, Melissa; Dileepan, Kottarappat N.; Wood, John G.

    2016-01-01

    Mast cells are immune cells of the myeloid lineage and are present in connective tissues throughout the body. The activation and degranulation of mast cells significantly modulates many aspects of physiological and pathological conditions in various settings. With respect to normal physiological functions, mast cells are known to regulate vasodilation, vascular homeostasis, innate and adaptive immune responses, angiogenesis, and venom detoxification. On the other hand, mast cells have also been implicated in the pathophysiology of many diseases, including allergy, asthma, anaphylaxis, gastrointestinal disorders, many types of malignancies, and cardiovascular diseases. This review summarizes the current understanding of the role of mast cells in many pathophysiological conditions. PMID:26779180

  4. Ancient origin of mast cells.

    PubMed

    Wong, G William; Zhuo, Lisheng; Kimata, Koji; Lam, Bing K; Satoh, Nori; Stevens, Richard L

    2014-08-22

    The sentinel roles of mammalian mast cells (MCs) in varied infections raised the question of their evolutionary origin. We discovered that the test cells in the sea squirt Ciona intestinalis morphologically and histochemically resembled cutaneous human MCs. Like the latter, C. intestinalis test cells stored histamine and varied heparin·serine protease complexes in their granules. Moreover, they exocytosed these preformed mediators when exposed to compound 48/80. In support of the histamine data, a C. intestinalis-derived cDNA was isolated that resembled that which encodes histidine decarboxylase in human MCs. Like heparin-expressing mammalian MCs, activated test cells produced prostaglandin D2 and contained cDNAs that encode a protein that resembles the synthase needed for its biosynthesis in human MCs. The accumulated morphological, histochemical, biochemical, and molecular biology data suggest that the test cells in C. intestinalis are the counterparts of mammalian MCs that reside in varied connective tissues. The accumulated data point to an ancient origin of MCs that predates the emergence of the chordates >500million years ago, well before the development of adaptive immunity. The remarkable conservation of MCs throughout evolution is consistent with their importance in innate immunity. PMID:25094046

  5. Mast cells as targets of pimecrolimus.

    PubMed

    Ma, Zhongcai; Jiao, Zongjiu

    2011-11-01

    Mast cells, the multi-functional secretory cells, are the pivotal effector cells in immune response, and contribute to the pathogenesis of many diverse diseases, like asthma and mastocytosis, by releasing numerous proinflammatory mediators. Pimecrolimus (SDZ ASM 981) is a derivative of the macrolactam ascomycin and is a member of the calcineurin inhibitor class of immunosuppressors. It inhibits the calcineurin-dependent activation of nuclear factor of activated T cells and the expression of a number of proinflammatory cytokines in turn. Pimecrolimus has high and selective anti-inflammatory activity within the skin, and with much lower potential to affect local and systemic immune responses. Therefore it has been widely used for treatment of various inflammatory skin diseases. It has a cellselective mode of action, and mast cells are its specific target cells. Pimecrolimus inhibits the release of both preformed and de novo synthesized mediators from activated mast cells and inhibits accumulation of mast cells by inducing apoptosis. Several experimental and clinical reports have demonstrated the successful application of pimecrolimus and other calcineurin inhibitors, such as tacrolimus and cyclosporine A, to treat mastocytosis, a spectrum of disorders characterized by mast cell hyperplasia, especially cutaneous mastocytosis. These new findings suggest that pimecrolimus and other calcineurin inhibitors may be a novel and effective therapeutic approach for mast cell-associated diseases such as asthma and mastocytosis. PMID:22114844

  6. Benign mast cell hyperplasia and atypical mast cell infiltrates in penile lichen planus in adult men.

    PubMed

    Regauer, Sigrid; Beham-Schmid, Christine

    2014-08-01

    Introduction. Lichen planus (LP) is a chronic cytokine-mediated disease of possible auto-immune etiology. 25% of men have anogenital manifestations. Erosive penile LP causes a scarring phimosis of the foreskin in uncircumcised men. Mast cells as potent immune modulators have been implicated in a number of autoimmune and chronic inflammatory diseases, but have not been investigated in LP. Material and Methods. Formalin-fixed tissues of 117 circumcision specimens of adult men affected by LP were evaluated for the extent of mast cell and lymphocyte infiltrates, characterized immunohistochemically with antibodies to CD 3, 4, 8, 20, 21, 25, 30, 117c and human mast cell tryptase. Specimens with dense mast cell infiltrates were analyzed for point mutations of the c-kit gene (D816V). Results. Unaffected skin and modified mucosa of foreskins contained ⟨5 mast cells/mm². The inflammatory infiltrate of LP-lesions displayed ⟨15 mast cells/mm² in 33/117 foreskins, 16-40 mast cells/mm² in 22/117 and ⟩40 mast cells/mm² (average 70, range 40-100) in 62/117 foreskins. Lesional mast cells of 29/117 (24%) foreskins showed aberrant CD25-expression and/or spindled morphology, with 11/29 men having erosive LP, 13/29 a lymphocytic vasculitis and 1/28 a systemic mastocytosis. Neither CD30-expression nor c-kit mutations were identified. Atypical mast cell infiltrates in LP correlated with high disease activity, erosive LP and presence of lymphocytic vasculitis Conclusions. Increased mast cells in penile LP, mostly representing a benign hyperplasia/activation syndrome, suggests them as targets for innovative therapy options for symptomatic LP-patients not responding to corticosteroid therapy. Presently, the biological implications of atypical mast cell infiltrates in penile LP are unknown. PMID:24402730

  7. Mast cell leukemia: an extremely rare disease.

    PubMed

    Lu, Dai-Yin; Gau, Jyh-Pyng; Hong, Ying-Chung; Liu, Chun-Yu; Yu, Yuan-Bin; Hsiao, Liang-Tsai; Liu, Jin-Hwang; Chen, Po-Min; Chiou, Tzeon-Jye; Tzeng, Cheng-Hwai

    2014-08-01

    Systemic mastocytosis is characterized by pathologic proliferation and accumulation of mast cells in at least one extracutaneous organ such as liver, spleen, bone marrow, or lymph nodes. The clinical features are highly variable depending on impairment of the involved organ systems. It often raises diagnostic challenges. Here we report a case of a 78-year-old patient with mast cell leukemia. The literature is reviewed regarding the diagnosis and updated management of this rare disease. PMID:25028296

  8. Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.

    PubMed

    Drube, Sebastian; Weber, Franziska; Loschinski, Romy; Beyer, Mandy; Rothe, Mandy; Rabenhorst, Anja; Göpfert, Christiane; Meininger, Isabel; Diamanti, Michaela A; Stegner, David; Häfner, Norman; Böttcher, Martin; Reinecke, Kirstin; Herdegen, Thomas; Greten, Florian R; Nieswandt, Bernhard; Hartmann, Karin; Krämer, Oliver H; Kamradt, Thomas

    2015-03-10

    Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca²⁺-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term "subthreshold IKK activation".This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33.We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo.Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure. PMID:25749030

  9. Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

    PubMed Central

    Drube, Sebastian; Beyer, Mandy; Rothe, Mandy; Rabenhorst, Anja; Göpfert, Christiane; Meininger, Isabel; Diamanti, Michaela A.; Stegner, David; Häfner, Norman; Böttcher, Martin; Reinecke, Kirstin; Herdegen, Thomas; Greten, Florian R.; Nieswandt, Bernhard; Hartmann, Karin; Krämer, Oliver H.; Kamradt, Thomas

    2015-01-01

    Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2+-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term “subthreshold IKK activation”. This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure. PMID:25749030

  10. Modulation of mast cell and basophil functions by benzene metabolites.

    PubMed

    Triggiani, Massimo; Loffredo, Stefania; Granata, Francescopaolo; Staiano, Rosaria I; Marone, Gianni

    2011-11-01

    Benzene is a carcinogenic compound used in industrial manufacturing and a common environmental pollutant mostly derived from vehicle emissions and cigarette smoke. Benzene exposure is associated with a variety of clinical conditions ranging from hematologic diseases to chronic lung disorders. Beside its direct toxicity, benzene exerts multiple effects after being converted to reactive metabolites such as hydroquinone and benzoquinone. Mast cells and basophils are primary effector cells involved in the development of respiratory allergies such as rhinitis and bronchial asthma and they play an important role in innate immunity. Benzene and its metabolites can influence mast cell and basophil responses either directly or by interfering with other cells, such as T cells, macrophages and monocytes, which are functionally connected to mast cells and basophils. Hydroquinone and benzoquinone inhibit the release of preformed mediators, leukotriene synthesis and cytokine production in human basophils stimulated by IgE- and non IgE-mediated agonists. Furthermore, these metabolites reduce IgE-mediated degranulation of mast cells and the development of allergic lung inflammation in rats. Both in vitro and in vivo studies indicate that benzene metabolites alter biochemical and functional activities of other immunocompetent cells and may impair immune responses in the lung. These inhibitory effects of benzene metabolites are primarily mediated by interference with early transduction signals such as PI3 kinase. Together, currently available studies indicate that benzene metabolites interfere by multiple mechanisms with the role of basophils and mast cells in innate immunity and in chronic inflammation in the lung. PMID:22103854

  11. Signal transduction and chemotaxis in mast cells.

    PubMed

    Draber, Petr; Halova, Ivana; Polakovicova, Iva; Kawakami, Toshiaki

    2016-05-01

    Mast cells play crucial roles in both innate and adaptive arms of the immune system. Along with basophils, mast cells are essential effector cells for allergic inflammation that causes asthma, allergic rhinitis, food allergy and atopic dermatitis. Mast cells are usually increased in inflammatory sites of allergy and, upon activation, release various chemical, lipid, peptide and protein mediators of allergic reactions. Since antigen/immunoglobulin E (IgE)-mediated activation of these cells is a central event to trigger allergic reactions, innumerable studies have been conducted on how these cells are activated through cross-linking of the high-affinity IgE receptor (FcεRI). Development of mature mast cells from their progenitor cells is under the influence of several growth factors, of which the stem cell factor (SCF) seems to be the most important. Therefore, how SCF induces mast cell development and activation via its receptor, KIT, has been studied extensively, including a cross-talk between KIT and FcεRI signaling pathways. Although our understanding of the signaling mechanisms of the FcεRI and KIT pathways is far from complete, pharmaceutical applications of the knowledge about these pathways are underway. This review will focus on recent progresses in FcεRI and KIT signaling and chemotaxis. PMID:25941081

  12. Mast Cells Mediate Acute Kidney Injury through the Production of TNF

    PubMed Central

    Summers, Shaun A.; Chan, Jacky; Gan, Poh-Yi; Dewage, Lakshi; Nozaki, Yuji; Steinmetz, Oliver M.; Nikolic-Paterson, David J.; Kitching, A. Richard

    2011-01-01

    Leukocyte recruitment contributes to acute kidney injury (AKI), but the mechanisms by which leukocytes promote injury are not completely understood. The degranulation of mast cells releases inflammatory molecules, including TNF, but whether these cells participate in the pathogenesis of AKI is unknown. Here, we induced AKI with cisplatin in mast cell-deficient and wild-type mice. Compared with wild-type mice, deficiency of mast cells attenuated renal injury, reduced serum levels of TNF, and reduced recruitment of leukocytes to the inflamed kidney. Mast cell-deficient mice also exhibited significantly lower intrarenal expression of leukocyte chemoattractants. Mast cell-deficient mice reconstituted with mast cells from wild-type mice exhibited similar cisplastin-induced renal damage and serum levels of TNF as wild-type mice. In contrast, mast cell-deficient mice reconstituted with mast cells from TNF-deficient mice continued to demonstrate significant attenuation of cisplatin-induced renal injury. Furthermore, the mast-cell stabilizer sodium chromoglycate also significantly abrogated renal injury in this model of AKI. Taken together, these results suggest that mast cells mediate AKI through the production of TNF. PMID:22021718

  13. Mast Cell-Mediated Mechanisms of Nociception

    PubMed Central

    Aich, Anupam; Afrin, Lawrence B.; Gupta, Kalpna

    2015-01-01

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner. PMID:26690128

  14. Do mast cells link obesity and asthma?

    PubMed Central

    Sismanopoulos, Nikolaos; Delivanis, Danae-Anastasia; Mavrommati, Despina; Hatziangelaki, Erifille; Conti, Pio; Theoharides, Theoharis C.

    2012-01-01

    Asthma is a chronic inflammatory disease of the lungs. Both the number of cases and severity of asthma have been increasing without a clear explanation. Recent evidence suggests that obesity, which has also been increasing alarmingly, may worsen or precipitate asthma, but there is little evidence of how obesity may contribute to lung inflammation. We propose that mast cells are involved in both asthma and obesity by being the target and source of adipocytokines, “alarmins” such as interleukin-9 (IL-9) and interleukin-33 (IL-33), and stress molecules including corticotropin-releasing hormone (CRH) and neurotensin (NT), secreted in response to the metabolic burden. In particular, CRH and NT have synergistic effects on mast cell secretion of vascular endothelial growth factor (VEGF). IL-33 augments VEGF release induced by substance P (SP) and tumor necrosis factor (TNF) release induced by NT. Both IL-9 and IL-33 also promote lung mast cell infiltration and augment allergic inflammation. These molecules are also expressed in human mast cells leading to autocrine effects. Obese patients are also less sensitive to glucocorticoids and bronchodilators. Development of effective mast cell inhibitors may be a novel approach for the management of both asthma and obesity. Certain flavonoid combinations may be a promising new treatment approach. PMID:23066905

  15. Characterization of Mast Cell Secretory Granules and Their Cell Biology

    PubMed Central

    Azouz, Nurit Pereg; Hammel, Ilan

    2014-01-01

    Exocytosis and secretion of secretory granule (SG) contained inflammatory mediators is the primary mechanism by which mast cells exert their protective immune responses in host defense, as well as their pathological functions in allergic reactions and anaphylaxis. Despite their central role in mast cell function, the molecular mechanisms underlying the biogenesis and secretion of mast cell SGs remain largely unresolved. Early studies have established the lysosomal nature of the mast cell SGs and implicated SG homotypic fusion as an important step occurring during both their biogenesis and compound secretion. However, the molecular mechanisms that account for key features of this process largely remain to be defined. A novel high-resolution imaging based methodology allowed us to screen Rab GTPases for their phenotypic and functional impact and identify Rab networks that regulate mast cell secretion. This screen has identified Rab5 as a novel regulator of homotypic fusion of the mast cell SGs that thereby regulates their size and cargo composition. PMID:24988214

  16. Vaccine adjuvants: Tailor-made mast-cell granules

    NASA Astrophysics Data System (ADS)

    Gunzer, Matthias

    2012-03-01

    Mast cells induce protective immune responses through secretion of stimulatory granules. Microparticles modelled after mast-cell granules are now shown to replicate and enhance the functions of their natural counterparts and to direct the character of the resulting immunity.

  17. A role for mast cells in the development of adjuvant-induced vasculitis and arthritis.

    PubMed Central

    Johnston, B.; Burns, A. R.; Kubes, P.

    1998-01-01

    The objective of this study was to characterize the role of mast cells in the development of vasculitis and joint swelling in adjuvant-immunized rats. Leukocyte trafficking within mesenteric venules (rolling and adhesion) and mast cell activation (ruthenium red uptake) were examined in vivo. Elevated leukocyte trafficking was observed by 4 days after immunization, whereas joint swelling developed between days 10 and 12. Perivascular mast cells took up ruthenium red and appeared activated by electron microscopy at 4 but not 12 days after immunization. Treatment with the mast cell stabilizer cromolyn on days 1 to 4 after immunization blocked ruthenium red uptake at day 4 and reduced leukocyte rolling and adhesion by approximately 50%. This treatment also reduced rolling, adhesion, and joint swelling at day 12 by approximately 50%. Cromolyn treatment over days 9 to 12 reduced joint swelling but increased leukocyte emigration into the mesentery. Peritoneal mast cells isolated 4 days after immunization elicited significant neutrophil chemotaxis in vitro, whereas day 12 mast cells did not. Mast cell activation and vasculitis were absent in adjuvant-resistant Fisher/344 rats. These data suggest that mast cells play an early role in the initiation of vasculitis and may function by day 12 to limit infiltration of leukocytes from the vasculature. In the joint, however, mast cells appear to contribute to inflammation at early as well as later time points. Images Figure 2 PMID:9466582

  18. Mast cells mediate acute inflammatory responses to implanted biomaterials

    PubMed Central

    Tang, Liping; Jennings, Timothy A.; Eaton, John W.

    1998-01-01

    Implanted biomaterials trigger acute and chronic inflammatory responses. The mechanisms involved in such acute inflammatory responses can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces. We earlier observed that two chemokines—macrophage inflammatory protein 1α/monocyte chemoattractant protein 1—and the phagocyte integrin Mac-1 (CD11b/CD18)/surface fibrinogen interaction are, respectively, required for phagocyte chemotaxis and adherence to biomaterial surfaces. However, it is still not clear how the initial transmigration of phagocytes through the endothelial barrier into the area of the implant is triggered. Because implanted biomaterials elicit histaminic responses in the surrounding tissue, and histamine release is known to promote rapid diapedesis of inflammatory cells, we evaluated the possible role of histamine and mast cells in the recruitment of phagocytes to biomaterial implants. Using i.p. and s.c. implantation of polyethylene terephthalate disks in mice we find: (i) Extensive degranulation of mast cells, accompanied by histamine release, occurs adjacent to short-term i.p. implants. (ii) Simultaneous administration of H1 and H2 histamine receptor antagonists (pyrilamine and famotidine, respectively) greatly diminishes recruitment and adhesion of both neutrophils (<20% of control) and monocytes/macrophages (<30% of control) to implants. (iii) Congenitally mast cell-deficient mice also exhibit markedly reduced accumulation of phagocytes on both i.p. and s.c implants. (iv) Finally, mast cell reconstitution of mast cell-deficient mice restores “normal” inflammatory responses to biomaterial implants. We conclude that mast cells and their granular products, especially histamine, are important in recruitment of inflammatory cells to biomaterial implants. Improved knowledge of such responses may permit purposeful modulation of both acute and chronic inflammation affecting implanted biomaterials. PMID

  19. Momordica charantia (Bitter Melon) Reduces Obesity-Associated Macrophage and Mast Cell Infiltration as well as Inflammatory Cytokine Expression in Adipose Tissues

    PubMed Central

    Zhang, Lei; Na Xu, Yan Lin; Wang, Xin; Liu, Jian; Qu, Wei

    2013-01-01

    Obesity is a world-wide epidemic disease that correlates closely with type 2 diabetes and cardiovascular diseases. Obesity-induced chronic adipose tissue inflammation is now considered as a critical contributor to the above complications. Momordica charantia (bitter melon, BM) is a traditional Chinese food and well known for its function of reducing body weight gain and insulin resistance. However, it is unclear whether BM could alleviate adipose tissue inflammation caused by obesity. In this study, C57BL/6 mice were fed high fat diet (HFD) with or without BM for 12 weeks. BM-contained diets ameliorated HFD-induced obesity and insulin resistance. Histological and real-time PCR analysis demonstrated BM not only reduced macrophage infiltration into epididymal adipose tissues (EAT) and brown adipose tissues (BAT). Flow cytometry show that BM could modify the M1/M2 phenotype ratio of macrophages in EAT. Further study showed that BM lowered mast cell recruitments in EAT, and depressed pro-inflammatory cytokine monocyte chemotactic protein-1 (MCP-1) expression in EAT and BAT as well as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression in EAT. Finally, ELISA analysis showed BM-contained diets also normalized serum levels of the cytokines. In summary, in concert with ameliorated insulin resistance and fat deposition, BM reduced adipose tissue inflammation in diet-induced obese (DIO) mice. PMID:24358329

  20. Momordica charantia (Bitter Melon) reduces obesity-associated macrophage and mast cell infiltration as well as inflammatory cytokine expression in adipose tissues.

    PubMed

    Bao, Bin; Chen, Yan-Guang; Zhang, Lei; Na Xu, Yan Lin; Wang, Xin; Liu, Jian; Qu, Wei

    2013-01-01

    Obesity is a world-wide epidemic disease that correlates closely with type 2 diabetes and cardiovascular diseases. Obesity-induced chronic adipose tissue inflammation is now considered as a critical contributor to the above complications. Momordica charantia (bitter melon, BM) is a traditional Chinese food and well known for its function of reducing body weight gain and insulin resistance. However, it is unclear whether BM could alleviate adipose tissue inflammation caused by obesity. In this study, C57BL/6 mice were fed high fat diet (HFD) with or without BM for 12 weeks. BM-contained diets ameliorated HFD-induced obesity and insulin resistance. Histological and real-time PCR analysis demonstrated BM not only reduced macrophage infiltration into epididymal adipose tissues (EAT) and brown adipose tissues (BAT). Flow cytometry show that BM could modify the M1/M2 phenotype ratio of macrophages in EAT. Further study showed that BM lowered mast cell recruitments in EAT, and depressed pro-inflammatory cytokine monocyte chemotactic protein-1 (MCP-1) expression in EAT and BAT as well as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression in EAT. Finally, ELISA analysis showed BM-contained diets also normalized serum levels of the cytokines. In summary, in concert with ameliorated insulin resistance and fat deposition, BM reduced adipose tissue inflammation in diet-induced obese (DIO) mice. PMID:24358329

  1. Phosphatidylinositol-3-kinase regulates mast cell ion channel activity.

    PubMed

    Lam, Rebecca S; Shumilina, Ekaterina; Matzner, Nicole; Zemtsova, Irina M; Sobiesiak, Malgorzata; Lang, Camelia; Felder, Edward; Dietl, Paul; Huber, Stephan M; Lang, Florian

    2008-01-01

    Stimulation of the mast cell IgE-receptor (FcepsilonRI) by antigen leads to stimulation of Ca(2+) entry with subsequent mast cell degranulation and release of inflammatory mediators. Ca(2+) further activates Ca(2+)-activated K(+) channels, which in turn provide the electrical driving force for Ca(2+) entry. Since phosphatidylinositol (PI)-3-kinase has previously been shown to be required for mast cell activation and degranulation, we explored, whether mast cell Ca(2+) and Ca(2+)-activated K(+) channels may be sensitive to PI3-kinase activity. Whole-cell patch clamp experiments and Fura-2 fluorescence measurements for determination of cytosolic Ca(2+) concentration were performed in mouse bone marrow-derived mast cells either treated or untreated with the PI3-kinase inhibitors LY-294002 (10 muM) and wortmannin (100 nM). Antigen-stimulated Ca(2+) entry but not Ca(2+) release from the intracellular stores was dramatically reduced upon PI3-kinase inhibition. Ca(2+) entry was further inhibited by TRPV blocker ruthenium red (10 muM). Ca(2+) entry following readdition after Ca(+)-store depletion with thapsigargin was again decreased by LY-294002, pointing to inhibition of store-operated channels (SOCs). Moreover, inhibition of PI3-kinase abrogated IgE-stimulated, but not ionomycin-induced stimulation of Ca(2+)-activated K(+) channels. These observations disclose PI3-kinase-dependent regulation of Ca(2+) entry and Ca(2+)-activated K(+)-channels, which in turn participate in triggering mast cell degranulation. PMID:18769043

  2. Mast cells in airway diseases and interstitial lung disease.

    PubMed

    Cruse, Glenn; Bradding, Peter

    2016-05-01

    Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease. PMID:25959386

  3. Choroidal mast cells in retinal pathology: a potential target for intervention.

    PubMed

    Bousquet, Elodie; Zhao, Min; Thillaye-Goldenberg, Brigitte; Lorena, Viera; Castaneda, Beatriz; Naud, Marie Christine; Bergin, Ciara; Besson-Lescure, Bernadette; Behar-Cohen, Francine; de Kozak, Yvonne

    2015-08-01

    Mast cells are important in the initiation of ocular inflammation, but the consequences of mast cell degranulation on ocular pathology remain uncharacterized. We induced mast cell degranulation by local subconjunctival injection of compound 48/80. Initial degranulation of mast cells was observed in the choroid 15 minutes after the injection and increased up to 3 hours after injection. Clinical signs of anterior segment inflammation paralleled mast cell degranulation. With the use of optical coherence tomography, dilation of choroidal vessels and serous retinal detachments (SRDs) were observed and confirmed by histology. Subconjunctival injection of disodium cromoglycate significantly reduced the rate of SRDs, demonstrating the involvement of mast cell degranulation in posterior segment disorders. The infiltration of polymorphonuclear and macrophage cells was associated with increased ocular media concentrations of tumor necrosis factor-α, CXCL1, IL-6, IL-5, chemokine ligand 2, and IL-1β. Analysis of the amounts of vascular endothelial growth factor and IL-18 showed an opposite evolution of vascular endothelial growth factor compared with IL-18 concentrations, suggesting that they regulate each other's production. These findings suggest that the local degranulation of ocular mast cells provoked acute ocular inflammation, dilation, increased vascular permeability of choroidal vessels, and SRDs. The involvement of mast cells in retinal diseases should be further investigated. The pharmacologic inhibition of mast cell degranulation may be a potential target for intervention. PMID:26166807

  4. A protective role of mast cells in intestinal tumorigenesis.

    PubMed

    Sinnamon, Mark J; Carter, Kathy J; Sims, Lauren P; Lafleur, Bonnie; Fingleton, Barbara; Matrisian, Lynn M

    2008-04-01

    Mast cells have been observed in numerous types of tumors; however, their role in carcinogenesis remains poorly understood. The majority of epidemiological evidence suggests a negative association between the presence of mast cells and tumor progression in breast, lung and colonic neoplasms. Intestinal adenomas in the multiple intestinal neoplasia (Min, APC(Min/+)) mouse displayed increased numbers of mast cells and increased abundance of mast cell-associated proteinases as determined by transcriptional profiling with the Hu/Mu ProtIn microarray. To examine the role of mast cells in intestinal tumorigenesis, a mutant mouse line deficient in mast cells, Sash mice (c-kit(W-sh/W-sh)), was crossed with the Min mouse, a genetic model of intestinal neoplasia. The resulting mast cell-deficient Min-Sash mice developed 50% more adenomas than littermate controls and the tumors were 33% larger in Min-Sash mice. Mast cell deficiency did not affect tumor cell proliferation; however, apoptosis was significantly inhibited in mast cell-deficient mice. Mast cells have been shown to act as critical upstream regulators of numerous inflammatory cells. Neutrophil, macrophage and T cell populations were similar between Min and Min-Sash mice; however, eosinophils were significantly less abundant in tumors obtained from Min-Sash animals. These results indicate a protective, antitumor role of mast cells in a genetic model of early-stage intestinal tumorigenesis. PMID:18258601

  5. Vitamin D3 represses IgE-dependent mast cell activation via mast cell-CYP27B1 and -vitamin D receptor activity

    PubMed Central

    Yip, Kwok-Ho; Kolesnikoff, Natasha; Yu, Chunping; Hauschild, Nicholas; Taing, Houng; Biggs, Lisa; Goltzman, David; Gregory, Philip A.; Anderson, Paul H.; Samuel, Michael S.; Galli, Stephen J.; Lopez, Angel F.; Grimbaldeston, Michele A.

    2014-01-01

    Background Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to what extent 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), or its predominant inactive precursor metabolite in circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. Objective We sought to assess whether the vitamin D3 metabolites, 25OHD3 and 1α,25(OH)2D3, can repress IgE-dependent mast cell activation via mast cell-CYP27B1 and -vitamin D receptor activity. Methods We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D3-induced curtailment of PCA responses in WBB6F1-KitW/W-v or C57BL/6J-KitW-sh/W-sh mice engrafted with mast cells that did or did not express VDR or CYP27B1. Results Here we show that mouse and human mast cells can convert 25OHD3 to 1α,25(OH)2D3 via 25-hydroxyvitamin D-1α–hydroxylase (CYP27B1) activity, and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell-derived pro-inflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin D3 metabolites significantly reduced the magnitude of skin swelling associated IgE-mediated PCA reactions in vivo; a response that required functional mast cell-VDRs and mast cell-CYP27B1. Conclusion Taken together, our findings provide a mechanistic explanation for the anti-inflammatory effects of vitamin D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo. PMID:24461581

  6. Mast Cells Synthesize, Store, and Release Nerve Growth Factor

    NASA Astrophysics Data System (ADS)

    Leon, A.; Buriani, A.; dal Toso, R.; Fabris, M.; Romanello, S.; Aloe, L.; Levi-Montalcini, R.

    1994-04-01

    Mast cells and nerve growth factor (NGF) have both been reported to be involved in neuroimmune interactions and tissue inflammation. In many peripheral tissues, mast cells interact with the innervating fibers. Changes in the behaviors of both of these elements occur after tissue injury/inflammation. As such conditions are typically associated with rapid mast cell activation and NGF accumulation in inflammatory exudates, we hypothesized that mast cells may be capable of producing NGF. Here we report that (i) NGF mRNA is expressed in adult rat peritoneal mast cells; (ii) anti-NGF antibodies clearly stain vesicular compartments of purified mast cells and mast cells in histological sections of adult rodent mesenchymal tissues; and (iii) medium conditioned by peritoneal mast cells contains biologically active NGF. Mast cells thus represent a newly recognized source of NGF. The known actions of NGF on peripheral nerve fibers and immune cells suggest that mast cell-derived NGF may control adaptive/reactive responses of the nervous and immune systems toward noxious tissue perturbations. Conversely, alterations in normal mast cell behaviors may provoke maladaptive neuroimmune tissue responses whose consequences could have profound implications in inflammatory disease states, including those of an autoimmune nature.

  7. Mast cells: potential positive and negative roles in tumor biology.

    PubMed

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. PMID:24777963

  8. Mast cells control insulitis and increase Treg cells to confer protection against STZ-induced type 1 diabetes in mice.

    PubMed

    Carlos, Daniela; Yaochite, Juliana N U; Rocha, Fernanda A; Toso, Vanina D; Malmegrim, Kelen C R; Ramos, Simone G; Jamur, Maria C; Oliver, Constance; Camara, Niels O; Andrade, Marcus V M; Cunha, Fernando Q; Silva, João S

    2015-10-01

    Quantitative alterations in mast cell numbers in pancreatic lymph nodes (PLNs) have been reported to be associated with type 1 diabetes (T1D) progression, but their potential role during T1D remains unclear. In this study, we evaluated the role of mast cells in T1D induced by multiple low-dose streptozotocin (MLD-STZ) treatments, using two strains of mast cell-deficient mice (W/W(v) or Wsh/Wsh) and the adoptive transfer of mast cells. Mast cell deficient mice developed severe insulitis and accelerated hyperglycemia, with 100% of mice becoming diabetic compared to their littermates. In parallel, these diabetic mice had decreased numbers of T regulatory (Treg) cells in the PLNs. Additionally, mast cell deficiency caused a significant reduction in IL-10, TGF-β, and IL-6 expression in the pancreatic tissue. Interestingly, IL-6-deficient mice are more susceptible to T1D associated with reduced Treg-cell numbers in the PLNs, but mast cell transfer from wild-type mice induced protection to T1D in these mice. Finally, mast cell adoptive transfer prior to MLD-STZ administration conferred resistance to T1D, promoted increased Treg cells, and decreased IL-17-producing T cells in the PLNs. Taken together, our results indicate that mast cells are implicated in resistance to STZ-induced T1D via an immunological tolerance mechanism mediated by Treg cells. PMID:26234742

  9. Mast Cells Regulate Wound Healing in Diabetes.

    PubMed

    Tellechea, Ana; Leal, Ermelindo C; Kafanas, Antonios; Auster, Michael E; Kuchibhotla, Sarada; Ostrovsky, Yana; Tecilazich, Francesco; Baltzis, Dimitrios; Zheng, Yongjun; Carvalho, Eugénia; Zabolotny, Janice M; Weng, Zuyi; Petra, Anastasia; Patel, Arti; Panagiotidou, Smaro; Pradhan-Nabzdyk, Leena; Theoharides, Theoharis C; Veves, Aristidis

    2016-07-01

    Diabetic foot ulceration is a severe complication of diabetes that lacks effective treatment. Mast cells (MCs) contribute to wound healing, but their role in diabetes skin complications is poorly understood. Here we show that the number of degranulated MCs is increased in unwounded forearm and foot skin of patients with diabetes and in unwounded dorsal skin of diabetic mice (P < 0.05). Conversely, postwounding MC degranulation increases in nondiabetic mice, but not in diabetic mice. Pretreatment with the MC degranulation inhibitor disodium cromoglycate rescues diabetes-associated wound-healing impairment in mice and shifts macrophages to the regenerative M2 phenotype (P < 0.05). Nevertheless, nondiabetic and diabetic mice deficient in MCs have delayed wound healing compared with their wild-type (WT) controls, implying that some MC mediator is needed for proper healing. MCs are a major source of vascular endothelial growth factor (VEGF) in mouse skin, but the level of VEGF is reduced in diabetic mouse skin, and its release from human MCs is reduced in hyperglycemic conditions. Topical treatment with the MC trigger substance P does not affect wound healing in MC-deficient mice, but improves it in WT mice. In conclusion, the presence of nondegranulated MCs in unwounded skin is required for proper wound healing, and therapies inhibiting MC degranulation could improve wound healing in diabetes. PMID:27207516

  10. Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis.

    PubMed

    Gan, Poh-Yi; O'Sullivan, Kim M; Ooi, Joshua D; Alikhan, Maliha A; Odobasic, Dragana; Summers, Shaun A; Kitching, A Richard; Holdsworth, Stephen R

    2016-05-01

    Observations in experimental murine myeloperoxidase (MPO)-ANCA-associated vasculitis (AAV) show mast cells degranulate, thus enhancing injury as well as producing immunomodulatory IL-10. Here we report that, compared with biopsy specimens from control patients, renal biopsy specimens from 44 patients with acute AAV had more mast cells in the interstitium, which correlated with the severity of tubulointerstitial injury. Furthermore, most of the mast cells were degranulated and spindle-shaped in patients with acute AAV, indicating an activated phenotype. We hypothesized that the mast cell stabilizer disodium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production. We induced anti-MPO GN by immunizing mice with MPO and a low dose of anti-glomerular basement membrane antibody. When administered before or after induction of MPO autoimmunity in these mice, disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and development of GN, without diminishing IL-10 production. In contrast, administration of disodium cromoglycate to mast cell-deficient mice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4(+) effector T cell proliferation was enhanced by co-culture with mast cells, but in the presence of disodium cromoglycate, proliferation was inhibited and IL-10 production was enhanced. These results indicate that disodium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunomodulatory role of these cells. Thus as a therapeutic, disodium cromoglycate may substantially enhance the regulatory role of mast cells in MPO-AAV. PMID:26374606

  11. The SNARE Machinery in Mast Cell Secretion

    PubMed Central

    Lorentz, Axel; Baumann, Anja; Vitte, Joana; Blank, Ulrich

    2012-01-01

    Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators – stored in granules – as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion. PMID:22679448

  12. Hymenoptera Allergy and Mast Cell Activation Syndromes.

    PubMed

    Bonadonna, Patrizia; Bonifacio, Massimiliano; Lombardo, Carla; Zanotti, Roberta

    2016-01-01

    Mast cell activation syndrome (MCAS) can be diagnosed in patients with recurrent, severe symptoms from mast cell (MC)-derived mediators, which are transiently increased in serum and are attenuated by mediator-targeting drugs. When KIT-mutated, clonal MC are detected in these patients, a diagnosis of primary MCAS can be made. Severe systemic reactions to hymenoptera venom (HV) represent the most common form of anaphylaxis in patients with mastocytosis. Patients with primary MCAS and HV anaphylaxis are predominantly males and do not have skin lesions in the majority of cases, and anaphylaxis is characterized by hypotension and syncope in the absence of urticaria and angioedema. A normal value of tryptase (≤11.4 ng/ml) in these patients does not exclude a diagnosis of mastocytosis. Patients with primary MCAS and HV anaphylaxis have to undergo lifelong venom immunotherapy, in order to prevent further potentially fatal severe reactions. PMID:26714690

  13. Mast cells and their activation in lung disease.

    PubMed

    Virk, Harvinder; Arthur, Greer; Bradding, Peter

    2016-08-01

    Mast cells and their activation contribute to lung health via innate and adaptive immune responses to respiratory pathogens. They are also involved in the normal response to tissue injury. However, mast cells are involved in disease processes characterized by inflammation and remodeling of tissue structure. In these diseases mast cells are often inappropriately and chronically activated. There is evidence for activation of mast cells contributing to the pathophysiology of asthma, pulmonary fibrosis, and pulmonary hypertension. They may also play a role in chronic obstructive pulmonary disease, acute respiratory distress syndrome, and lung cancer. The diverse mechanisms through which mast cells sense and interact with the external and internal microenvironment account for their role in these diseases. Newly discovered mechanisms of redistribution and interaction between mast cells, airway structural cells, and other inflammatory cells may offer novel therapeutic targets in these disease processes. PMID:26845625

  14. Twenty-first century mast cell stabilizers

    PubMed Central

    Finn, D F; Walsh, J J

    2013-01-01

    Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically to prevent allergic reactions to common allergens. Despite the relative success of the most commonly prescribed mast cell stabilizer, disodium cromoglycate, in use for the preventative treatment of bronchial asthma, allergic conjunctivitis and vernal keratoconjunctivitis, there still remains an urgent need to design new substances that are less expensive and require less frequent dosing schedules. In this regard, recent developments towards the discovery of the next generation of mast cell stabilizing drugs has included studies on substances isolated from natural sources, biological, newly synthesized compounds and drugs licensed for other indications. The diversity of natural products evaluated range from simple phenols, alkaloids, terpenes to simple amino acids. While in some cases their precise mode of action remains unknown it has nevertheless sparked interest in the development of synthetic derivatives with improved pharmacological properties. Within the purely synthetic class of inhibitors, particular attention has been devoted to the inhibition of important signalling molecules including spleen TK and JAK3. The statin class of cholesterol-lowering drugs as well as nilotinib, a TK inhibitor, are just some examples of clinically used drugs that have been evaluated for their anti-allergic properties. Here, we examine each approach under investigation, summarize the test data generated and offer suggestions for further preclinical evaluation before their therapeutic potential can be realized. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23441583

  15. Creatine phosphokinase in rat mast cells.

    PubMed Central

    Magro, A M

    1980-01-01

    The soluble cytoplasmic fraction of an homogenate from peritoneal rat mast cells, demonstrated a considerable amount of catalytic activity which promotes the transfer of phosphate from creatine phosphate to ADP. The plasma membrane, mitochondrial and microsomal fractions show negligible amounts of the catalyst. Enzyme activity is maximal at 37 degrees showing little activity below 17 degrees or above 45 degrees. The enzyme is strongly Mg2+-dependent, whereas it is only slightly activated by Ca2+. pH values between 7 and 8 are optimal and the enzyme is irreversibly inactivated below pH 4. The overall behaviour of the catalyst indicates it to be a creatine phosphokinase (CPK), an enzyme considered important to muscle and nerve tissues. The CPK is probably not encapsulated within the mast cells' perigranular membranes and is retained in the soluble cytoplasm during exocytosis. The possible role of CPK, as to whether it is assisting in maintaining proper levels of intracellular ATP during exocytosis, and/or whether it is associated with components of the mast cells' contractile apparatus, is discussed. PMID:6160090

  16. Mast cell activation syndrome masquerading as agranulocytosis.

    PubMed

    Afrin, Lawrence B

    2012-01-01

    Acquired agranulocytosis is a rare, life-threatening disorder. The few known causes/associations usually are readily identifiable (e.g., drug reaction, Felty syndrome, megaloblastosis, large granular lymphocytic leukemia, etc.). We report a novel association with mast cell disease. A 61-year-old morbidly obese man developed rheumatoid arthritis unresponsive to several medications. Agranulocytosis developed shortly after sulfasalazine was started but did not improve when the drug was soon stopped. Other symptoms across many systems developed including hives and presyncope. Marrow aspiration and biopsy showed only neutropenia. Serum tryptase was mildly elevated; urinary prostaglandin D2 was markedly elevated. Other causes were not found. Mast cell activation syndrome (MCAS) was diagnosed. Oral antihistamines, montelukast, and cromolyn were unhelpful; aspirin was initially felt contraindicated. Imatinib immediately increased neutrophils from 0% to 25% but did not help symptoms; subsequent addition of aspirin increased neutrophils further and abated symptoms. Different presentations of different MCAS patients reflect elaboration of different mediators likely consequent to different Kit mutations. Mast cells (MCs) help regulate adipocytes, and adipocytes can inhibit granulopoiesis; thus, a Kit-mutated MC clone may have directly and/or indirectly driven agranulocytosis. MCAS should be considered in otherwise idiopathic agranulocytosis presenting with comorbidities best explained by MC mediator release. PMID:22338992

  17. Inhibition of mast cells by algae.

    PubMed

    Price, Joseph A; Sanny, Charles; Shevlin, Dennis

    2002-01-01

    There is a history of use of algae as foods and as food additives, or nutraceuticals. Although algae are a safe component of human foods and animal feeds, the effects of the algae other than as a source of protein are not clear. We examined the prevalence of an antiinflammatory activity in selected algae using, as an assay system, the inhibition of histamine release from mast cells. Methanolic extracts of eleven algae were examined for activity to inhibit the release of histamine from mast cells in vitro. This activity was found widely among the samples tested. The activities of these extracts were not uniformly stable in acid methanol. Selected extracts studied further did not separate with the use of size-exclusion filtration filters. LH-20 chromatography suggested at least two main elution areas of activity of the Chlorella extract. In summary, we saw wide phylogenetic dispersion of mast cell inhibition activity, suggesting that this antiinflammatory property is common in algae. This effect was apparently due to multiple activities within the algal extracts. PMID:12639395

  18. Rat Embryonic Mast Cells Originate in the AGM

    PubMed Central

    Guiraldelli, Michel Farchi; França, Carolina Nunes; de Souza, Devandir Antonio; da Silva, Elaine Zayas Marcelino; Toso, Vanina Danuza; Carvalho, Celiane Cardoso; Jamur, Maria Célia; Oliver, Constance

    2013-01-01

    Mast cells originate from pluripotent hematopoietic stem cells. Two mast cell specific antibodies, mAbsAA4 and BGD6, have previously been used to identify and study committed mast cell precursors (MCcps) in the bone marrow of adult mice and rats. However, the embryonic origin of MCcps is still not known. In the present study, we identified MCcps in rat embryos using these previously characterized mast cell specific antibodies. The MCcps were found in the AGM (aorta-gonad-mesonephros) region of rat embryos at E11.5. These cells were BGD6+, CD34+, c-kit+, CD13+, FcεRI−, AA4− CD40−, and Thy-1−. By PCR the cells contained message for the α and β subunits of FcεRI and mast cell specific proteases. In vitro, the MCcps differentiated into metachromatic mast cells. With age of gestation the percent of MCcps diminished while the percent of mast cell progenitors increased. An increased knowledge of the biology and embryonic origin of mast cells may contribute to a greater understanding of allergy, asthma, and other mast cell related diseases. PMID:23505443

  19. A20-Deficient Mast Cells Exacerbate Inflammatory Responses In Vivo

    PubMed Central

    Vahl, J. Christoph; Aszodi, Attila; Peschke, Katrin; Schenten, Dominik; Hammad, Hamida; Beyaert, Rudi; Saur, Dieter; van Loo, Geert; Roers, Axel; Lambrecht, Bart N.; Kool, Mirjam; Schmidt-Supprian, Marc

    2014-01-01

    Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function. PMID:24453940

  20. Mast Cell-Deficient W-sash c-kit Mutant KitW-sh/W-sh Mice as a Model for Investigating Mast Cell Biology in Vivo

    PubMed Central

    Grimbaldeston, Michele A.; Chen, Ching-Cheng; Piliponsky, Adrian M.; Tsai, Mindy; Tam, See-Ying; Galli, Stephen J.

    2005-01-01

    Mice carrying certain mutations in the white spotting (W) locus (ie, c-kit) exhibit reduced c-kit tyrosine kinase-dependent signaling that results in mast cell deficiency and other phenotypic abnormalities. The c-kit mutations in KitW/W-v mice impair melanogenesis and result in anemia, sterility, and markedly reduced levels of tissue mast cells. In contrast, KitW-sh/W-sh mice, bearing the W-sash (Wsh) inversion mutation, have mast cell deficiency but lack anemia and sterility. We report that adult KitW-sh/W-sh mice had a profound deficiency in mast cells in all tissues examined but normal levels of major classes of other differentiated hematopoietic and lymphoid cells. Unlike KitW/W-v mice, KitW-sh/W-sh mice had normal numbers of TCRγδ intraepithelial lymphocytes in the intestines and did not exhibit a high incidence of idiopathic dermatitis, ulcers, or squamous papillomas of the stomach, but like KitW/W-v mice, they lacked interstitial cells of Cajal in the gut and exhibited bile reflux into the stomach. Systemic or local reconstitution of mast cell populations was achieved in nonirradiated adult KitW-sh/W-sh mice by intravenous, intraperitoneal, or intradermal injection of wild-type bone marrow-derived cultured mast cells but not by transplantation of wild-type bone marrow cells. Thus, KitW-sh/W-sh mice represent a useful model for mast cell research, especially for analyzing mast cell function in vivo. PMID:16127161

  1. Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo.

    PubMed

    Grimbaldeston, Michele A; Chen, Ching-Cheng; Piliponsky, Adrian M; Tsai, Mindy; Tam, See-Ying; Galli, Stephen J

    2005-09-01

    Mice carrying certain mutations in the white spotting (W) locus (ie, c-kit) exhibit reduced c-kit tyrosine kinase-dependent signaling that results in mast cell deficiency and other phenotypic abnormalities. The c-kit mutations in Kit(W/W-v) mice impair melanogenesis and result in anemia, sterility, and markedly reduced levels of tissue mast cells. In contrast, Kit(W-sh/W-sh) mice, bearing the W-sash (W(sh)) inversion mutation, have mast cell deficiency but lack anemia and sterility. We report that adult Kit(W-sh/W-sh) mice had a profound deficiency in mast cells in all tissues examined but normal levels of major classes of other differentiated hematopoietic and lymphoid cells. Unlike Kit(W/W-v) mice, Kit(W-sh/W-sh) mice had normal numbers of TCR gammadelta intraepithelial lymphocytes in the intestines and did not exhibit a high incidence of idiopathic dermatitis, ulcers, or squamous papillomas of the stomach, but like Kit(W/W-v) mice, they lacked interstitial cells of Cajal in the gut and exhibited bile reflux into the stomach. Systemic or local reconstitution of mast cell populations was achieved in nonirradiated adult Kit(W-sh/W-sh) mice by intravenous, intraperitoneal, or intradermal injection of wild-type bone marrow-derived cultured mast cells but not by transplantation of wild-type bone marrow cells. Thus, Kit(W-sh/W-sh) mice represent a useful model for mast cell research, especially for analyzing mast cell function in vivo. PMID:16127161

  2. Partial Protection against Helicobacter pylori in the Absence of Mast Cells in Mice▿

    PubMed Central

    Ding, Hua; Nedrud, John G.; Wershil, Barry; Redline, Raymond W.; Blanchard, Thomas G.; Czinn, Steven J.

    2009-01-01

    The goal of this study is to evaluate the contribution of mast cells to Helicobacter pylori immunity in a model of vaccine-induced protection. Mast cell-deficient KitlSl/KitlSl-d and control mice were immunized with H. pylori sonicate plus cholera toxin and challenged with H. pylori, and the bacterial loads, inflammatory infiltrates, and cytokine responses were evaluated and compared at 1, 2, and 4 weeks postchallenge. In vitro stimulation assays were performed using bone marrow-derived mast cells, and recall assays were performed with spleen cells of immunized mast cell-deficient and wild-type mice. Bacterial clearance was observed by 2 weeks postchallenge in mast cell-deficient mice. The bacterial load was reduced by 4.0 log CFU in wild-type mice and by 1.5 log CFU in mast cell-deficient mice. Neutrophil numbers in the gastric mucosa of immune KitlSl/KitlSl-d mice were lower than those for immune wild-type mice (P < 0.05). Levels of gastric interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α) were also significantly lower in immune KitlSl/KitlSl-d mice than in wild-type mice (P < 0.001). Immunized mast cell-deficient and wild-type mouse spleen cells produced IFN-γ and IL-17 in response to H. pylori antigen stimulation. TNF-α and CXC chemokines were detected in mast cell supernatants after 24 h of stimulation with H. pylori antigen. The results indicate that mast cells are not essential for but do contribute to vaccine-induced immunity and that mast cells contribute to neutrophil recruitment and inflammation in response to H. pylori. PMID:19822650

  3. Mast cells in the sheep, hedgehog and rat forebrain

    PubMed Central

    MICHALOUDI, HELEN C.; PAPADOPOULOS, GEORGIOS C.

    1999-01-01

    The study was designed to reveal the distribution of various mast cell types in the forebrain of the adult sheep, hedgehog and rat. Based on their histochemical and immunocytochemical characteristics, mast cells were categorised as (1) connective tissue-type mast cells, staining metachromatically purple with the toluidine blue method, or pale red with the Alcian blue/safranin method, (2) mucosal-type or immature mast cells staining blue with the Alcian blue/safranin method and (3) serotonin immunopositive mast cells. All 3 types of brain mast cells in all species studied were located in both white and grey matter, often associated with intraparenchymal blood vessels. Their distribution pattern exhibited interspecies differences, while their number varied considerably not only between species but also between individuals of each species. A distributional left-right asymmetry, with more cells present on the left side, was observed in all species studied but it was most prominent in the sheep brain. In the sheep, mast cells were abundantly distributed in forebrain areas, while in the hedgehog and the rat forebrain, mast cells were less widely distributed and were relatively or substantially fewer in number respectively. A limited number of brain mast cells, in all 3 species, but primarily in the rat, were found to react both immunocytochemically to 5-HT antibody and histochemically with Alcian blue/safranin staining. PMID:10634696

  4. Mast cell chymase in experimentally induced psoriasis.

    PubMed

    Suttle, Mireille-Maria; Harvima, Ilkka T

    2016-06-01

    Mast cell chymase can have a pro-inflammatory or an immunosuppressive function in psoriasis, but the outcome may depend on the level of chymase activity. Therefore, mast cells showing chymase activity (Chyact ) and immunoreactivity (Chyprot ) were studied during the Köbner reaction (0 days, 2 h, 1 day, 3 days and 7 days) of psoriasis induced by the tape-stripping technique. Also, the effect of recombinant human chymase (rh-chymase) or human LAD2 mast cells (LAD2) on the (3) H-thymidine uptake of psoriatic peripheral blood mononuclear cells (PBMC) or total T cells was studied. The Chyact /Chyprot ratio tended to be higher in all time-point biopsies in the Köbner-negative (n = 10) than -positive (n = 8) group (P = 0.073), although chymase activity decreased significantly at 2 h to 1 day only in the Köbner-negative group. rh-chymase (0.05-0.5 μg/mL) stimulated to a varying extent PBMC in eight out of nine cultures, but in all cultures 5 μg/mL rh-chymase turned the stimulation towards inhibition. The effect of rh-chymase on T cells varied from stimulation to inhibition, but in 11 of 15 cultures rh-chymase, at least at 5 μg/mL, produced a change to inhibition. In co-cultures, LAD2 inhibited PBMC in the absence of soybean trypsin inhibitor (SBTI). In the presence of SBTI, LAD2 stimulated PBMC in the majority of seven cultures. In summary, the psoriatic immunopathogenesis may be promoted at low, but controlled at high, activity status of chymase. PMID:26703925

  5. Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses.

    PubMed

    Law, Mankit; Lee, YongChan; Morales, J Luis; Ning, Gang; Huang, Weishan; Pabon, Jonathan; Kannan, Arun K; Jeong, Ah-Reum; Wood, Amie; Carter, Chavez; Mohinta, Sonia; Song, Jihong; August, Avery

    2015-07-15

    Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo. PMID:26056254

  6. Melatonin protects mast cells against cytotoxicity mediated by chemical stimuli PMACI: possible clinical use.

    PubMed

    Maldonado, M D; Garcia-Moreno, H; Calvo, J R

    2013-09-15

    Melatonin has documented cytoprotective effects on a wide variety of immune cells. The mechanism of action on mast cells (RBL-2H3) still remains in the dark. We found that melatonin significantly attenuated phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-induced cytotoxicity in a concentration and time-dependent manner. It appears that the effect of melatonin on mast cells is two-fold: dependent (MT1 and MT2) and independent membrane receptors. In conclusion, melatonin treatment reduced the cytotoxicity, mediated by PMACI, and could provide a useful therapeutic option in processes where an excessive activation of mast cells occurs. PMID:23870536

  7. Rab11 Regulates the Mast Cell Exocytic Response.

    PubMed

    Wilson, Joshua D; Shelby, Sarah A; Holowka, David; Baird, Barbara

    2016-09-01

    Stimulated exocytic events provide a means for physiological communication and are a hallmark of the mast cell-mediated allergic response. In mast cells these processes are triggered by antigen crosslinking of IgE bound to its high-affinity receptor, FcϵRI, on the cell surface. Here we use the endosomal v-SNARE VAMP8, and the lysosomal hydrolase β-hexosaminidase (β-Hex), each C-terminally fused to super-ecliptic pHluorin, to monitor stimulated exocytosis. Using these pHluorin-tagged constructs, we monitor stimulated exocytosis by fluorimetry and visualize individual exocytic events with total internal reflection (TIRF) microscopy. Similar to constitutive recycling endosome (RE) trafficking, we find that stimulated RE exocytosis, monitored by VAMP8, is attenuated by expression of dominant negative (S25N) Rab11. Stimulated β-Hex exocytosis is also reduced in the presence of S25N Rab11, suggesting that expression of this mutant broadly impacts exocytosis. Interestingly, pretreatment with inhibitors of actin polymerization, cytochalasin D or latrunculin A, substantially restores both RE and lysosome exocytosis in cells expressing S25N Rab11. Conversely, stabilizing F-actin with jasplakinolide inhibits antigen-stimulated exocytosis but is not additive with S25N Rab11-mediated inhibition, suggesting that these reagents inhibit related processes. Together, our results suggest that Rab11 participates in the regulation necessary for depolymerization of the actin cytoskeleton during stimulated exocytosis in mast cells. PMID:27288050

  8. Amarogentin Displays Immunomodulatory Effects in Human Mast Cells and Keratinocytes

    PubMed Central

    Wölfle, Ute; Haarhaus, Birgit; Schempp, Christoph M.

    2015-01-01

    Keratinocytes express the bitter taste receptors TAS2R1 and TAS2R38. Amarogentin as an agonist for TAS2R1 and other TAS2Rs promotes keratinocyte differentiation. Similarly, mast cells are known to express bitter taste receptors. The aim of this study was to assess whether bitter compounds display immunomodulatory effects on these immunocompetent cells in the skin, so that they might be a target in chronic inflammatory diseases such as atopic dermatitis and psoriasis. Here, we investigated the impact of amarogentin on substance P-induced release of histamine and TNF-α from the human mast cell line LAD-2. Furthermore, the effect of amarogentin on HaCaT keratinocytes costimulated with TNF-α and histamine was investigated. Amarogentin inhibited in LAD-2 cells substance P-induced production of newly synthesized TNF-α, but the degranulation and release of stored histamine were not affected. In HaCaT keratinocytes histamine and TNF-α induced IL-8 and MMP-1 expression was reduced by amarogentin to a similar extent as with azelastine. In conclusion amarogentin displays immunomodulatory effects in the skin by interacting with mast cells and keratinocytes. PMID:26600671

  9. Acrolein induction of oxidative stress and degranulation in mast cells.

    PubMed

    Hochman, Daniel J; Collaco, Christopher R; Brooks, Edward G

    2014-08-01

    Increases in asthma worldwide have been associated epidemiologically with expanding urban air pollution. The mechanistic relationship between airway hyper-responsiveness, inflammation, and ambient airborne triggers remains ambiguous. Acrolein, a ubiquitous aldehyde pollutant, is a product of incomplete combustion reactions. Acrolein is abundant in cigarette smoke, effluent from industrial smokestacks, diesel exhaust, and even hot oil cooking vapors. Acrolein is a potent airway irritant and can induce airway hyper-responsiveness and inflammation in the lungs of animal models. In the present study, we utilized the mast cell analog, RBL-2H3, to interrogate the responses of cells relevant to airway inflammation and allergic responses as a model for the induction of asthma-like conditions upon exposure to acrolein. We hypothesized that acrolein would induce oxidative stress and degranulation in airway mast cells. Our results indicate that acrolein at 1 ppm initiated degranulation and promoted the generation of reactive oxygen species (ROS). Introduction of antioxidants to the system significantly reduced both ROS generation and degranulation. At higher levels of exposure (above 100 ppm), RBL-2H3 cells displayed signs of severe toxicity. This experimental data indicates acrolein can induce an allergic inflammation in mast cell lines, and the initiation of degranulation was moderated by the application of antioxidants. PMID:23047665

  10. Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells

    PubMed Central

    Lopes, José Pedro; Stylianou, Marios; Nilsson, Gunnar; Urban, Constantin F.

    2015-01-01

    Immunosuppressed patients are frequently afflicted with severe mycoses caused by opportunistic fungal pathogens. Besides being a commensal, colonizing predominantly skin and mucosal surfaces, Candida albicans is the most common human fungal pathogen. Mast cells are present in tissues prone to fungal colonization being expectedly among the first immune cells to get into contact with C. albicans. However, mast cell-fungus interaction remains a neglected area of study. Here we show that human mast cells mounted specific responses towards C. albicans. Collectively, mast cell responses included the launch of initial, intermediate and late phase components determined by the secretion of granular proteins and cytokines. Initially mast cells reduced fungal viability and occasionally internalized yeasts. C. albicans could evade ingestion by intracellular growth leading to cellular death. Furthermore, secreted factors in the supernatants of infected cells recruited neutrophils, but not monocytes. Late stages were marked by the release of cytokines that are known to be anti-inflammatory suggesting a modulation of initial responses. C. albicans-infected mast cells formed extracellular DNA traps, which ensnared but did not kill the fungus. Our results suggest that mast cells serve as tissue sentinels modulating antifungal immune responses during C. albicans infection. Consequently, these findings open new doors for understanding fungal pathogenicity. PMID:26192381

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

    PubMed Central

    Xu, Jia-Ming

    2012-01-01

    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. PMID:22240242

  12. The adaptor 3BP2 is required for KIT receptor expression and human mast cell survival

    PubMed Central

    Ainsua-Enrich, Erola; Serrano-Candelas, Eva; Álvarez-Errico, Damiana; Picado, César; Sayós, Joan; Rivera, Juan; Martín, Margarita

    2015-01-01

    3BP2 is a cytoplasmic adaptor protein that acts as a positive regulator in mast cell FcεRI-dependent signaling. The KIT receptor whose ligand is the stem cell factor (SCF) is necessary for mast cell development, proliferation and survival as well as for optimal IgE-dependent signal. Activating mutations in KIT have been associated with several diseases including mastocytosis. In the present work, we found that 3BP2 silencing impairs KIT signaling pathways, thus affecting PI3K and MAP kinase pathways in human mast cells from HMC-1, LAD2 (human mast cell lines) and CD34+-derived mast cells. Unexpectedly, silencing of 3BP2 reduces KIT expression in normal human mast cells as well as in HMC-1 cells where KIT is mutated, thus increasing cellular apoptosis and caspase 3/7 activity. 3BP2 silencing reduces KIT transcription expression levels. Interestingly, 3BP2 silencing decreased MITF expression, a transcription factor involved in KIT expression. Reconstitution of 3BP2 in knockdown cells leads to reversal of KIT expression as well as survival phenotype. Accordingly MITF reconstitution enhances KIT expression levels in 3BP2 silenced cells. Moreover, downregulation of KIT expression by miRNA221 overexpression or the proteasome inhibitor bortezomib also reduced 3BP2 and MITF expression. Furthermore, KIT tyrosine activity inhibition reduced 3BP2 and MITF expression, demonstrating again a tight and reciprocal relationship between these molecules. Taken together, our results show that 3BP2 regulates human mast cell survival and participates in KIT-mediated signal transduction by directly controlling KIT receptor expression, suggesting its potential as a therapeutic target in mast cell-mediated inflammatory diseases and deregulated KIT disorders. PMID:25810396

  13. The Tec family kinase Itk differentially controls mast cell responses*

    PubMed Central

    Iyer, Archana S.; August, Avery

    2008-01-01

    The Tec family tyrosine kinase Itk is expressed in T cells and mast cells. Mice lacking Itk exhibit impaired TH2 cytokine secretion; however, they have increased circulating serum IgE but exhibit few immunological symptoms of allergic airway responses. We have examined the role of Itk in mast cell function and FcεRI signaling. We report here that Itk null mice have reduced allergen/IgE induced histamine release as well as early airway hyperresponsiveness in vivo. This is due to the increased levels of IgE in the serum of these mice, since the transfer of Itk null BMMC into mast cell deficient W/Wv animals is able to fully rescue histamine release in the W/Wv mice. Further analysis of Itk null BMMC in vitro revealed that while they have normal degranulation responses, they secrete elevated levels of cytokines, including IL-13 and TNF-α, particularly in response to unliganded IgE. Analysis of biochemical events downstream of the FcεRI revealed little difference in overall tyrosine phosphorylation of specific substrates or calcium responses, however, these cells express elevated levels of NFAT which was largely nuclear. Our results suggest that the reduced mast cell response in vivo in Itk null mice is due to elevated levels of IgE in these mice. Our results also suggest that Itk differentially modulates mast cell degranulation and cytokine production in part by regulating expression and activation of NFAT proteins in these cells. “This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any

  14. Involvement of mast cells in the development of fibrosis in rats with postmyocarditis dilated cardiomyopathy.

    PubMed

    Palaniyandi Selvaraj, Suresh; Watanabe, Kenichi; Ma, Meilei; Tachikawa, Hitoshi; Kodama, Makoto; Aizawa, Yoshifusa

    2005-11-01

    Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Occurrence of myocardial fibrosis is an important event in the ventricular remodeling process, which takes place during DCM. Mast cells are well known inflammatory cells implicated in various biological phenomena. The involvement of mast cells in the development of myocardial fibrosis of DCM in rats after autoimmune myocarditis remains unknown. Nine-week-old male Lewis rats were immunized with cardiac myosin and divided into vehicle treated (group V) and disodium cromoglycate (DSCG), a mast cell stabilizer (24 mg/kg i.p.) treated (group DSCG) groups. The animals were sacrificed after 60 d of immunization. The myocardium was excised and preserved for histopathology and protein analysis. Myocardial levels of transforming growth factor (TGF) beta1 and collagen-III were quantified. Staining of mast cells was performed by toluidine blue. A significant correlation was obtained between myocardial fibrosis and cardiac mast cell density. DSCG reduced myocardial fibrosis besides preventing infiltration and degranulation of mast cells. Our findings confirm the active participation of mast cells in the progression of myocardial fibrosis in rats with postmyocarditis DCM. PMID:16272703

  15. Malignant mast cell tumor in an African hedgehog (Atelerix albiventris).

    PubMed

    Raymond, J T; White, M R; Janovitz, E B

    1997-01-01

    In November 1995, a malignant mast cell tumor (mastocytoma) was diagnosed in an adult African hedgehog (Atelerix albiventris) from a zoological park (West Lafayette, Indiana, USA). The primary mast cell tumor presented as a firm subcutaneous mass along the ventrum of the neck. Metastasis to the right submandibular lymph node occurred. PMID:9027702

  16. Mast cell tumor destruction by deionized water.

    PubMed

    Grier, R L; Di Guardo, G; Schaffer, C B; Pedrosa, B; Myers, R; Merkley, D F; Thouvenelle, M

    1990-07-01

    In a controlled study, malignant murine P815 mastocytoma cells exposed in vitro to distilled and deionized water died as a result of progressive swelling, degranulation, and membrane rupture. A 90% mean cell death occurred when cells obtained directly from culture were exposed to deionized water for 2 minutes. Of 6 cryopreserved malignant murine cell lines, which included Cloudman S91 melanoma, CMT-93 rectum carcinoma, MMT-06052 mammary carcinoma, and S-180 Sarcoma, only P815 mastocytoma and YAC-1 lymphoma were significantly (P less than 0.05) affected by hypotonic shock; Cloudman S91 melanoma cells were the most resistant. Mastocytoma cells were selectively killed by hypotonic solution, and lymphoma cells were also killed by isotonic saline solution. Local mast cell tumor (MCT) recurrence and percentage survival were evaluated in 12 cats (21 MCT) and 54 dogs (85 MCT) subjected to surgery alone or local infiltration of deionized water as an adjunct to surgery. Of all 16 incompletely excised MCT in cats, there was no local recurrence following injection. Four mast cell tumors (2 cats) regressed after being injected in situ. In dogs with clinical stage-I MCT, local recurrence was detected in 50% (5/10), but with injection after incomplete excision, local MCT recurrence was significantly (P less than 0.05) less (6.6%, 1/15). Percentage recurrence was significantly (P less than 0.05) less and survival significantly greater when incompletely excised grade-II MCT were injected. Mean follow-up period after surgery in cats and dogs was 35 and 23.4 months, respectively. PMID:2117868

  17. Mast cell stabilizers obviate high fat diet-induced renal dysfunction in rats.

    PubMed

    Reena; Kaur, Tajpreet; Kaur, Anudeep; Singh, Manjinder; Buttar, Harpal Singh; Pathak, Devendra; Singh, Amrit Pal

    2016-04-15

    The present study investigated the infiltration of mast cells into the kidney tissue and the preventive role of mast cell stabilizers against high fat diet (HFD)-induced renal injury in rats. The animals were fed on HFD (30% fat) for 12 consecutive weeks to induce renal injury. The HFD-induced obesity was assessed by calculating obesity index, adiposity index, and estimation of total cholesterol, triglycerides, and high density lipoproteins in plasma. The renal dysfunction was evaluated by measuring creatinine clearance, blood urea nitrogen, uric acid, electrolytes and microproteinuria. The oxidative stress in renal tissues was determined by myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation and reduced glutathione level. The systolic blood pressure (SBP) was monitored using non-invasive blood pressure measuring apparatus. Histamine and hydroxyproline contents were quantified in renal tissues. Gross histopathological changes, mast cell density and collagen deposition in the renal tissue was determined by means of histopathology. The mast cell stabilizers, sodium cromoglycate and ketotifen were administered daily for 12 weeks. The HFD fed rats demonstrated significant increase in lipid profile, kidney injury with marked increase in renal oxidative stress, SBP, mast cell density, histamine content and hydroxyproline content that was attenuated by sodium cromoglycate and ketotifen treatment. Hence, the novel findings of this investigation suggest that HFD induced mast cells infiltration into kidney tissue seems to play an important role in renal pathology, and treatment with mast cell stabilizers serves as potential therapy in management of HFD induced renal dysfunction in rats. PMID:26944217

  18. L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.

    PubMed

    Shimada, Yuka; Hasegawa, Minoru; Kaburagi, Yuko; Hamaguchi, Yasuhito; Komura, Kazuhiro; Saito, Eriko; Takehara, Kazuhiko; Steeber, Douglas A; Tedder, Thomas F; Sato, Shinichi

    2003-04-15

    Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions. PMID:12682269

  19. Roles and relevance of mast cells in infection and vaccination

    PubMed Central

    Fang, Yu; Xiang, Zou

    2016-01-01

    Abstract In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines. Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens. Here, we review the current understanding of the participation of mast cells in defense against infection. We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases. PMID:26565602

  20. Microbes taming mast cells: Implications for allergic inflammation and beyond.

    PubMed

    Forsythe, Paul

    2016-05-01

    There is increasing awareness of a relationship between our microbiota and the pathogenesis of allergy and other inflammatory diseases. In investigating the mechanisms underlying microbiota modulation of allergy the focus has been on the induction phase; alterations in the phenotype and function of antigen presenting cells, induction of regulatory T cells and shifts in Th1/Th2 balance. However there is evidence that microbes can influence the effector phase of disease, specifically that certain potentially beneficial bacteria can attenuate mast cell activation and degranulation. Furthermore, it appears that different non-pathogenic bacteria can utilize distinct mechanisms to stabilize mast cells, acting locally though direct interaction with the mast cell at mucosal sites or attenuating systemic mast cell dependent responses, likely through indirect signaling mechanisms. The position of mast cells on the frontline of defense against pathogens also suggests they may play an important role in fostering the host-microbiota relationship. Mast cells are also conduits of neuro-immuo-endocrine communication, suggesting the ability of microbes to modulate cell responses may have implications for host physiology beyond immunology. Further investigation of mast cell regulation by non-pathogenic or symbiotic bacteria will likely lead to a greater understanding of host microbiota interaction and the role of the microbiome in health and disease. PMID:26130124

  1. Novel Identified Receptors on Mast Cells

    PubMed Central

    Migalovich-Sheikhet, Helena; Friedman, Sheli; Mankuta, David; Levi-Schaffer, Francesca

    2012-01-01

    Mast cells (MC) are major participants in the allergic reaction. In addition they possess immunomodulatory roles in the innate and adaptive immune reactions. Their functions are modulated through a number of activating and inhibitory receptors expressed on their surface. This review deals with some of the most recently described receptors, their expression patterns, ligand(s), signal transduction mechanisms, possible cross-talk with other receptors and, last but not least, regulatory functions that the MC can perform based on their receptor expression in health or in disease. Where the receptor role on MC is still not clear, evidences from other hematopoietic cells expressing them is provided as a possible insight for their function on MC. Suggested strategies to modulate these receptors’ activity for the purpose of therapeutic intervention are also discussed. PMID:22876248

  2. A mast cell secretagogue, compound 48/80, prevents the accumulation of hyaluronan in lung tissue injured by ionizing irradiation

    SciTech Connect

    Nilsson, K.; Bjermer, L.; Hellstroem, S.H.; Henriksson, R.; Haellgren, R. )

    1990-02-01

    Irradiation with a single dose of 30 Grey on the basal regions of the lungs of Sprague-Dawley rats induced a peribronchial and alveolar inflammation. Infiltration of mast cells in the edematous alveolar interstitial tissue and also in the peribronchial tissue were characteristic features of the lesion. The appearance of mast cells was already seen 4 wk after irradiation and by weeks 6 to 8 there was a heavy infiltration. The staining properties suggested that they were connective tissue-type mast cells. The infiltration of mast cells was paralleled by an accumulation of hyaluronan (hyaluronic acid) in the alveolar interstitial tissue 6 and 8 wk after irradiation. The recovery of hyaluronan (HA) during bronchoalveolar lavage (BAL) of the lungs also increased at this time. Treatment with a mast cell secretagogue, compound 48/80, induced a distinct reduction of granulated mast cells in the alveolar tissue. Regular treatment with compound 48/80 from the time of irradiation considerably reduced the HA recovery during BAL and the HA accumulation in the interstitial tissue but did not affect the interstitial infiltration of mononuclear cells and polymorphonuclear leukocytes. By contrast, an accumulation of HA in the alveolar interstitial space was induced when compound 48/80 was given not until mast cell infiltration of the lung had started. The effects of compound 48/80 indicate that the connective tissue response after lung irradiation is dependent on whether or not mast cell degranulation is induced before or after the mast cell infiltration of the alveolar tissue.

  3. Systemic mast cell disease with splenic infarction: a case report.

    PubMed

    Maruyama, H; Sugihara, S; Ishihara, K; Sada, K; Tsutsumi, M; Tsujiuchi, T; Nakae, D; Konishi, Y

    1998-05-01

    An autopsy case of systemic mast cell disease (SMCD) without primary skin lesions in a 57-year-old Japanese male is described. Initially the patient was suspected of having liver cirrhosis or malignant lymphoma because of hepatomegaly and lymph node enlargement on admission. However, a lymph node biopsy and bone marrow aspiration conducted on his third admission indicated a SMCD because of the existence of metachromatic cell aggregates stained with toluidine blue. At autopsy, the diagnosis was confirmed because the proliferating cells were histochemically proven to be mast cells by naphthol AS.D chloroacetate esterase, Giemsa and alcian blue, in addition to toluidine blue staining. The intra-abdominal and retroperitoneal lymph nodes were replaced by mast cell aggregates, which caused the splenic infarction and bilateral hydronephrosis, with infiltration of mast cells into the spleen and kidneys also being apparent. Mast cell infiltration was similarly found in the bone marrow, liver, ileum and ascending colon. Immunohistochemically, the mast cells were positive for antibodies of alpha 1-antichymotrypsin, CD45 (LCA), CD43 (MT-1), CD45R (MB-1) and the oncoprotein c-kit. Electron microscopic examination using formalin-fixed tissue gave supportive evidence of a mast cell origin for the lesions. PMID:9704348

  4. Emerging concepts: mast cell involvement in allergic diseases.

    PubMed

    Modena, Brian D; Dazy, Kristen; White, Andrew A

    2016-08-01

    In a process known as overt degranulation, mast cells can release all at once a diverse array of products that are preformed and present within cytoplasmic granules. This occurs typically within seconds of stimulation by environmental factors and allergens. These potent, preformed mediators (ie, histamine, heparin, serotonin, and serine proteases) are responsible for the acute symptoms experienced in allergic conditions such as allergic conjunctivitis, allergic rhinitis, allergy-induced asthma, urticaria, and anaphylaxis. Yet, there is reason to believe that the actions of mast cells are important when they are not degranulating. Mast cells release preformed mediators and inflammatory cytokines for periods after degranulation and even without degranulating at all. Mast cells are consistently seen at sites of chronic inflammation, including nonallergic inflammation, where they have the ability to temper inflammatory processes and shape tissue morphology. Mast cells can trigger actions and chemotaxis in other important immune cells (eg, eosinophils and the newly discovered type 2 innate lymphocytes) that then make their own contributions to inflammation and disease. In this review, we will discuss the many known and theorized contributions of mast cells to allergic diseases, focusing on several prototypical allergic respiratory and skin conditions: asthma, chronic rhinosinusitis, aspirin-exacerbated respiratory disease, allergic conjunctivitis, atopic dermatitis, and some of the more common medication hypersensitivity reactions. We discuss traditionally accepted roles that mast cells play in the pathogenesis of each of these conditions, but we also delve into new areas of discovery and research that challenge traditionally accepted paradigms. PMID:26976119

  5. Impaired expression of the mitochondrial calcium uniporter suppresses mast cell degranulation.

    PubMed

    Furuno, Tadahide; Shinkai, Narumi; Inoh, Yoshikazu; Nakanishi, Mamoru

    2015-12-01

    Calcium ion (Ca(2+)) uptake into the mitochondrial matrix influences ATP production, Ca(2+) homeostasis, and apoptosis regulation. Ca(2+) uptake across the ion-impermeable inner mitochondrial membrane is mediated by the mitochondrial Ca(2+) uniporter (MCU) complex. The MCU complex forms a pore structure composed of several proteins. MCU is a Ca(2+)-selective channel in the inner-mitochondrial membrane that allows electrophoretic Ca(2+) entry into the matrix. Mitochondrial Ca(2+) uptake 1 (MICU1) functions as a Ca(2+)-sensing regulator of the MCU complex. Previously, by microscopic analysis at the single-cell level, we found that during mast cell activation, mitochondria capture cytosolic Ca(2+) in two steps. Consequently, mitochondrial Ca(2+) uptake likely plays a role in cellular function through cytosolic Ca(2+) buffering. Here, we investigate the role of MCU and MICU1 in mitochondrial Ca(2+) uptake and mast cell degranulation using MCU- and MICU1-knockdown (KD) mast cells. Whereas MCU- and MICU1-KD mast cells show normal proliferation rates and mitochondrial membrane potential, they exhibit slow and reduced cytosolic and mitochondrial Ca(2+) elevation after antigen stimulation. Moreover, β-hexosaminidase release induced by antigen was significantly suppressed in MCU-KD cells but not MICU1-KD cells. This suggests that both MCU and MICU1 are involved in mitochondrial Ca(2+) uptake in mast cells, while MCU plays a role in mast cell degranulation. PMID:26350567

  6. Role of mast cells in gastrointestinal mucosal defense.

    PubMed

    Penissi, Alicia B; Rudolph, María I; Piezzi, Ramón S

    2003-08-01

    The purpose of this review, based on studies from our laboratory as well as from others, is to summarize salient features of mast cell immunobiology and to describe their associations with gastrointestinal mucosal defense. Gastrointestinal mast cells are involved in many pathologic effects, such as food hypersensitivity. On the other hand, they also play a protective role in defense against parasitic and microbial infections. Thus, they have both positive and negative effects, but presently the mechanisms that control the balance of these various effects are poorly known. It has been suggested that stabilization of mast cells may be a key mechanism to protect the gastrointestinal tract from injury. Few molecules are known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity. These include zinc compounds, sodium cromoglycate, FPL 52694, ketotifen, aloe vera, certain flavonoids such as quercetin, some sulfated proteoglycans such as chondroitin sulfate and dehydroleucodine. Dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana Besser, exhibits anti-inflammatory and gastrointestinal cytoprotective action. The lactone stimulates mucus production, and inhibits histamine and serotonin release from intestinal mast cells. The lactone could act as a selective mast cell stabilizer by releasing cytoprotective factors and inhibiting pro-inflammatory mast cell mediators. PMID:14510234

  7. Optical imaging of fibrin deposition to elucidate participation of mast cells in foreign body responses

    PubMed Central

    Weng, Hong; Tang, Ewin N.; Baker, David W.; Tang, Liping

    2014-01-01

    Mast cell activation has been shown to be an initiator and a key determinant of foreign body reactions. However, there is no non-invasive method that can quantify the degree of implant-associated mast cell activation. Taking advantage of the fact that fibrin deposition is a hallmark of mast cell activation around biomaterial implants, a near infrared probe was fabricated to have high affinity to fibrin. Subsequent in vitro testing confirmed that this probe has high affinity to fibrin. Using a subcutaneous particle implantation model, we found significant accumulation of fibrin-affinity probes at the implant sites as early as 15 min following particle implantation. The accumulation of fibrin-affinity probes at the implantation sites could also be substantially reduced if anti-coagulant – heparin was administered at the implant sites. Further studies have shown that subcutaneous administration of mast cell activator – compound 48/80 – prompted the accumulation of fibrin-affinity probes. However, implant-associated fibrin-affinity probe accumulation was substantially reduced in mice with mast cell deficiency. The results show that our fibrin-affinity probes may serve as a powerful tool to monitor and measure the extent of biomaterial-mediated fibrin deposition and mast cell activation in vivo. PMID:24342726

  8. Mast cells mediate malignant pleural effusion formation

    PubMed Central

    Giannou, Anastasios D.; Marazioti, Antonia; Spella, Magda; Kanellakis, Nikolaos I.; Apostolopoulou, Hara; Psallidas, Ioannis; Prijovich, Zeljko M.; Vreka, Malamati; Zazara, Dimitra E.; Lilis, Ioannis; Papaleonidopoulos, Vassilios; Kairi, Chrysoula A.; Patmanidi, Alexandra L.; Giopanou, Ioanna; Spiropoulou, Nikolitsa; Harokopos, Vaggelis; Aidinis, Vassilis; Spyratos, Dionisios; Teliousi, Stamatia; Papadaki, Helen; Taraviras, Stavros; Snyder, Linda A.; Eickelberg, Oliver; Kardamakis, Dimitrios; Iwakura, Yoichiro; Feyerabend, Thorsten B.; Rodewald, Hans-Reimer; Kalomenidis, Ioannis; Blackwell, Timothy S.; Agalioti, Theodora; Stathopoulos, Georgios T.

    2015-01-01

    Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1β, which in turn induced pleural vasculature leakiness and triggered NF-κB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell–induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable. PMID:25915587

  9. Radiological features of systemic mast-cell disease.

    PubMed

    Huang, T Y; Yam, L T; Li, C Y

    1987-08-01

    Radiological studies were done on 23 patients with systemic mast-cell disease (SMCD). Significant changes occur most often in bones and less commonly in the gastrointestinal tract and other visceral organs. These changes may be related either to tissue infiltration by mast cells, or to the effect exerted on tissues by chemical mediators of the mast cells, although in some instances findings may be coincidental. Because the radiological changes are not unique to SMCD, their main value, in association with the clinical information, is in directing further studies for diagnostic confirmation and in estimating the extent of systemic involvement. PMID:3664176

  10. Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice

    PubMed Central

    Sun, Jiusong; Sukhova, Galina K.; Yang, Min; Wolters, Paul J.; MacFarlane, Lindsey A.; Libby, Peter; Sun, Chongxiu; Zhang, Yadong; Liu, Jian; Ennis, Terri L.; Knispel, Rebecca; Xiong, Wanfen; Thompson, Robert W.; Baxter, B. Timothy; Shi, Guo-Ping

    2007-01-01

    Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell–deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. KitW-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3+ T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow–derived mast cells from WT or TNF-α–/– mice, but not from IL-6–/– or IFN-γ–/– mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms. PMID:17932568

  11. Generation of leukotrienes by purified human lung mast cells.

    PubMed Central

    MacGlashan, D W; Schleimer, R P; Peters, S P; Schulman, E S; Adams, G K; Newball, H H; Lichtenstein, L M

    1982-01-01

    Although mediator release from mast cells and basophils plays a central role in the pathogenesis of human allergic disease, biochemical studies have been restricted to rat peritoneal mast cells and basophilic leukemia cells because they could be easily purified. We have used two new techniques of cell separation to purify human lung mast cells to 98% homogeneity. Lung cell suspensions were obtained by dispersion of chopped lung tissue with proteolytic enzymes. Mast cells were then purified from the suspensions by countercurrent centrifugal elutriation and affinity chromatography. The purified mast cells released both histamine and slow-reacting substance of anaphylaxis (SRS-A) (leukotriene C and D) during stimulation with goat anti-human IgE antibody. Moreover, these preparations were able to generate significant quantities of SRS-A (32 +/- 7 x 10(-17) LTD mole-equivalents/mast cell) at all stages of purification, indicating that a secondary cell is not necessary for the antigen-induced release of SRS. Images PMID:7119113

  12. Ripe fruit of Rubus coreanus inhibits mast cell-mediated allergic inflammation.

    PubMed

    Kim, Hui-Hun; Choi, Phil Hyung; Yoo, Jin-Su; Jeon, Hoon; Chae, Byeong-Suk; Park, Jeong-Suk; Kim, Sang-Hyun; Shin, Tae-Yong

    2012-02-01

    In this study, we investigated the effect of a water extract of the ripe fruits of Rubus coreanus Miq. (Rosaceae) (RFRC) on mast cell-mediated allergic inflammation and studied the possible mechanism of action. Mast cell-mediated allergic disease is involved in many diseases such as anaphylaxis, rhinitis, asthma and atopic dermatitis. RFRC dose-dependently inhibited compound 48/80-induced systemic anaphylaxis and serum histamine release in mice. RFRC reduced the immunoglobulin E (IgE)-mediated local allergic reaction, passive cutaneous anaphylaxis. RFRC attenuated histamine release from rat peritoneal mast cells and human mast cells by the reduction of intracellular calcium. RFRC decreased the phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187 (PMACI)-stimulated expression and secretion of pro-inflammatory cytokines in human mast cells. The inhibitory effect of RFRC on cytokine production was nuclear factor (NF)-κB- and mitogen-activated protein kinase (MAPK)-dependent. In addition, RFRC suppressed the activation of caspase-1. Our findings provide evidence that RFRC inhibits mast cell-derived allergic inflammatory reactions, and for the involvement of calcium, NF-κB, MAPKs and caspase-1 in these effects. Furthermore, in vivo and in vitro anti-allergic inflammatory effects of RFRC provide affirmative proof of a possible therapeutic application of this agent in allergic inflammatory diseases. PMID:22075758

  13. Physiological and pathophysiological functions of intestinal mast cells.

    PubMed

    Bischoff, Stephan C

    2009-07-01

    The normal gastrointestinal (GI) mucosa is equipped with mast cells that account for 2-3% of lamina propria cells under normal conditions. Mast cells are generally associated with allergic disease, and indeed, food allergy that manifests in the GI tract is usually mast cell dependent. On the other hand, mast cells have a number of physiological functions in the GI tract, namely regulatory functions such as control of blood flow and coagulation, smooth muscle contraction and peristalsis, and secretion of acid, electrolytes, and mucus by epithelial cells. One of the most intriguing functions of intestinal mast cells is their role in host defense against microbes like bacteria, viruses, or parasites. Mast cells recognize microbes by antibody-dependent mechanisms and through pattern-recognition receptors. They direct the subsequent immune response by attracting both granulocytes and lymphocytes to the site of challenge via paracrine cytokine release. Moreover, mast cells initiate, by releasing proinflammatory mediators, innate defense mechanisms such as enhanced epithelial secretion, peristalsis, and alarm programs of the enteric nervous This initiation can occur in response to a primary contact to the microbe or other danger signals, but becomes much more effective if the triggering antigen reappears and antibodies of the IgE or IgG type have been generated in the meantime by the specific immune system. Thus, mast cells operate at the interface between innate and adaptive immune responses to enhance the defense against pathogens and, most likely, the commensal flora. In this respect, it is important to note that mast cells are directly involved in controlling the function of the intestinal barrier that turned out to be a crucial site for the development of infectious and immune-mediated diseases. Hence, intestinal mast cells perform regulatory functions to maintain tissue homeostasis, they are involved in host defense mechanisms against pathogens, and they can induce

  14. Lysophosphatidic acid synthesis and phospholipid metabolism in rat mast cells

    SciTech Connect

    Fagan, D.L.

    1986-01-01

    The role of lysophosphatidic acid in mast cell response to antigen was investigated using an isolated rat serosal mast cell model. The cells were incubated with monoclonal murine immunoglobulin E to the dinitrophenyl hapten and prelabeled with /sup 32/P-orthophosphate or /sup 3/H-fatty acids. Lysophosphatidic acid was isolated form cell extracts by 2-dimensional thin-layer chromatography, and the incorporated radioactivity was assessed by liquid scintillation counting. Lysophosphatidic acid labeling with /sup 32/P was increased 2-4 fold within 5 minutes after the addition of antigen or three other mast cell agonists. Functional group analyses unequivocally showed that the labeled compound was lysophosphatidic acid. Lysophosphatidic acid synthesis was dependent on the activity of diacylglycerol lipase, suggesting formation from monoacylglycerol. In addition, the studies of lysophosphatidic acid synthesis suggest that the addition of antigen to mast cells may initiate more than one route of phospholipid degradation and resynthesis. Whatever the origin of lysophosphatidic acid, the results of this study demonstrated that lysophosphatidic acid synthesis is stimulated by a variety of mast cell agonists. Dose-response, kinetic, and pharmacologic studies showed close concordance between histamine release and lysophosphatidic acid labeling responses. These observations provide strong evidence that lysophosphatidic acid plays an important role in mast cell activation.

  15. Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

    SciTech Connect

    Kim, Hui-Hun; Park, Seung-Bin; Lee, Soyoung; Kwon, Taeg Kyu; Shin, Tae-Yong; Park, Pil-Hoon; Lee, Seung-Ho; Kim, Sang-Hyun

    2014-02-01

    A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited the expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H{sub 1} receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases.

  16. TSLP induces mast cell development and aggravates allergic reactions through the activation of MDM2 and STAT6.

    PubMed

    Han, Na-Ra; Oh, Hyun-A; Nam, Sun-Young; Moon, Phil-Dong; Kim, Do-Won; Kim, Hyung-Min; Jeong, Hyun-Ja

    2014-10-01

    Thymic stromal lymphopoietin (TSLP) is known to promote T helper type 2 cell-associated inflammation. Mast cells are major effector cells in allergic inflammatory responses. We noted that the population and maturation of mast cells were reduced in TSLP-deficient mice (TSLP-/-). Thus, we hypothesized that TSLP might affect mast cell development. We found that TSLP induced the proliferation and differentiation of mast cells from bone marrow progenitors. TSLP-induced mast cell proliferation was abolished by depletion of mouse double minute 2 (MDM2) and signal transducers and activators of transcription 6 (STAT6), as an upstream activator of MDM2. TSLP-/-, in particular, had a considerable deficit in the expression of MDM2 and STAT6. Also, the TSLP deficiency attenuated mast cell-mediated allergic reactions through the downregulation of STAT6 and MDM2. In an antibody microarray chip analysis, MDM2 expression was increased in atopic dermatitis patients. These observations indicate that TSLP is a factor for mast cell development, and that it aggravates mast cell-mediated immune responses. PMID:24751726

  17. Mast cells: new therapeutic target in helminth immune modulation.

    PubMed

    Vukman, K V; Lalor, R; Aldridge, A; O'Neill, S M

    2016-01-01

    Helminth infection and their secreted antigens have a protective role in many immune-mediated inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. However, studies have focused primarily on identifying immune protective mechanisms of helminth infection and their secreted molecules on dendritic cells and macrophages. Given that mast cells have been shown to be implicated in the pathogenesis and progression of many inflammatory disorders, their role should also be examined and considered as cellular target for helminth-based therapies. As there is a dearth of studies examining the interaction of helminth-derived antigens and mast cells, this review will focus on the role of mast cells during helminth infection and examine our current understanding of the involvement of mast cells in TH 1/TH 17-mediated immune disorders. In this context, potential mechanisms by which helminths could target the TH 1/TH 17 promoting properties of mast cells can be identified to unveil novel therapeutic mast cell driven targets in combating these inflammatory disorders. PMID:26577605

  18. Proton nuclear magnetic resonance studies of mast cell histamine

    SciTech Connect

    Rabenstein, D.L.; Ludowyke, R.; Lagunoff, D.

    1987-11-03

    The state of histamine in mast cells was studied by /sup 1/H NMR spectroscopy. Spectra were measured for histamine in situ in intact mast cells, for histamine in suspensions of mast cell granule matrices that had been stripped of their membranes, and for histamine in solutions of heparin. The /sup 1/H NMR spectrum of intact mast cells is relatively simple, consisting predominantly of resonances for intracellular histamine superimposed on a weaker background of resonances from heparin and proteins of the cells. All of the intracellular histamine contributes of the NMR signals, indicating it must be relatively mobile and not rigidly associated with the negatively charged granule matrix. Spectra for intracellular histamine and for histamine in granule matrices are similar, indicating the latter to be a reasonable model for the in situ situation. The dynamics of binding of histamine by granule matrices and by heparin are considerably different; exchange of histamine between the bulk water and the granule matrices is slow on the /sup 1/H NMR time scale, whereas exchange between the free and bound forms in heparin solution is fast. The chemical shifts of resonances for histamine in mast cells are pH dependent, decreasing as the intragranule pH increases without splitting or broadening. The results are interpreted to indicate that histamine in mast cells is relatively labile, with rapid exchange between histamine and pools of free histamine in water compartments confined in the granule matrix.

  19. Changes in numbers and types of mast cell colony-forming cells in the peritoneal cavity of mice after injection of distilled water: evidence that mast cells suppress differentiation of bone marrow-derived precursors

    SciTech Connect

    Kanakura, Y.; Kuriu, A.; Waki, N.; Nakano, T.; Asai, H.; Yonezawa, T.; Kitamura, Y.

    1988-03-01

    Two different types of cells in the peritoneal cavity of mice produce mast cell colonies in methylcellulose. Large mast cell colonies are produced by bone marrow-derived precursors resembling lymphoid cells by light microscopy (L-CFU-Mast), whereas medium and small mast cell colonies are produced by morphologically identifiable mast cells (M-CFU-Mast and S-CFU-Mast, respectively). In the present study we eradicated peritoneal mast cells by intraperitoneal (IP) injection of distilled water. The regeneration process was investigated to clarify the relationship between L-CFU-Mast, M-CFU-Mast, and S-CFU-Mast. After injection of distilled water, M-CFU-Mast and S-CFU-Mast disappeared, but L-CFU-Mast increased, and then M-CFU-Mast and S-CFU-Mast appeared, suggesting the presence of a hierarchic relationship. When purified peritoneal mast cells were injected two days after the water injection, the L-CFU-Mast did not increase. In the peritoneal cavity of WBB6F1-+/+ mice that had been lethally irradiated and rescued by bone marrow cells of C57BL/6-bgJ/bgJ (beige, Chediak-Higashi syndrome) mice, L-CFU-Mast were of bgJ/bgJ type, but M-CFU-Mast and S-CFU-Mast were of +/+ type. The injection of distilled water to the radiation chimeras resulted in the development of bgJ/bgJ-type M-CFU-Mast and then S-CFU-Mast. The presence of mast cells appeared to suppress the recruitment of L-CFU-Mast from the bloodstream and to inhibit the differentiation of L-CFU-Mast to M-CFU-Mast.

  20. Participation of mast cells in chronic otitis media.

    PubMed

    Pajor, Anna; Danilewicz, Marian; Jankowski, Andrzej; Durko, Tomasz

    2011-01-01

    In the pathogenesis of chronic otitis media (COM), much attention is paid to the molecular mechanisms of local inflammatory reactions in which mast cells (MCs) may be involved due to their role not only in allergic but also inflammatory processes. The aim of this study was to assess the density of mast cells in chronic otitis media in relationship to different clinical courses of COM, bacterial infections and types of disease. The MCs expression was measured immunohistochemically in paraffin-embedded granulation tissue specimens taken during surgery, by staining with a monoclonal antibody against tryptase. The density of tryptase-positive mast cells was lower in tissue samples from the group with a good clinical course than in those from the group with poor healing and recurrence (p = 0.006). There were no differences between the groups of patients with granulomatous and cholesteatomatous chronic otitis media (p = 0.66) or between the groups of patients with and without bacterial infection (p = 0.30), although the density of mast cells was lower for those with Pseudomonas aeruginosa/Proteus sp./ /Staphylococcus MRSA infection. In conclusion, the expression of mast cells in chronic otitis media granulation tissue was found to differ depending on the clinical course of the disease, but not on bacterial infection or type of COM. This may suggest that mast cells contribute to the maintenance of the inflammatory process, but not to antibacterial defense in chronic otitis media. PMID:22038229

  1. Modulatory Effects of Connexin-43 Expression on Gap Junction Intercellular Communications with Mast Cells and Fibroblasts

    PubMed Central

    Pistorio, Ashey L.; Ehrlich, H. Paul

    2011-01-01

    The influence of mast cells upon aberrant wound repair and excessive fibrosis has supportive evidence, but the mechanism for these mast cell activities is unclear. It is proposed that heterocellular gap junctional intercellular communication (GJIC) between fibroblasts and mast cells directs some fibroblast activities. An in vitro model was used employing a rodent derived peritoneal mast cell line (RMC-1) and human dermal derived fibroblasts. The influence of the expression of the gap junction channel structural protein, connexin 43 (Cx-43) on heterocellular GJIC, the expression of microtubule β-tubulin and microfilament α smooth muscle actin (SMA) were investigated. The knockdown of Cx-43 by siRNA in RMC-1 cells completely blocked GJIC between RMC-1 cells. SiRNA knockdown of Cx-43 within fibroblasts only dampened GJIC between fibroblasts. It appears Cx-43 is the only expressed connexin in RMC-1 cells. Fibroblasts express other connexins that participate in GJIC between fibroblasts in the absence of Cx-43 expression. Heterocellular GJIC between RMC-1 cells and fibroblasts transformed fibroblasts into myofibroblasts, expressing α SMA within cytoplasmic stress fibers. The knockdown of Cx-43 in RMC-1 cells increased β-tubulin expression, but its knockdown in fibroblasts reduced β-tubulin expression. Knocking down the expression of Cx-43 in fibroblasts limited α SMA expression. Cx-43 participation is critical for heterocellular GJIC between mast cells and fibroblasts, which may herald a novel direction for controlling fibrosis. PMID:21328609

  2. IL-10 Enhances IgE-Mediated Mast Cell Responses and Is Essential for the Development of Experimental Food Allergy in IL-10-Deficient Mice.

    PubMed

    Polukort, Stephanie H; Rovatti, Jeffrey; Carlson, Logan; Thompson, Chelsea; Ser-Dolansky, Jennifer; Kinney, Shannon R M; Schneider, Sallie S; Mathias, Clinton B

    2016-06-15

    IL-10 is a key pleiotropic cytokine that can both promote and curb Th2-dependent allergic responses. In this study, we demonstrate a novel role for IL-10 in promoting mast cell expansion and the development of IgE-mediated food allergy. Oral OVA challenge in sensitized BALB/c mice resulted in a robust intestinal mast cell response accompanied by allergic diarrhea, mast cell activation, and a predominance of Th2 cytokines, including enhanced IL-10 expression. In contrast, the development of intestinal anaphylaxis, including diarrhea, mast cell activation, and Th2 cytokine production, was significantly attenuated in IL-10(-/-) mice compared with wild-type (WT) controls. IL-10 also directly promoted the expansion, survival, and activation of mast cells; increased FcεRI expression on mast cells; and enhanced the production of mast cell cytokines. IL-10(-/-) mast cells had reduced functional capacity, which could be restored by exogenous IL-10. Similarly, attenuated passive anaphylaxis in IL-10(-/-) mice could be restored by IL-10 administration. The adoptive transfer of WT mast cells restored allergic symptoms in IL-10(-/-) mice, suggesting that the attenuated phenotype observed in these animals is due to a deficiency in IL-10-responding mast cells. Lastly, transfer of WT CD4 T cells also restored allergic diarrhea and intestinal mast cell numbers in IL-10(-/-) mice, suggesting that the regulation of IL-10-mediated intestinal mast cell expansion is T cell dependent. Our observations demonstrate a critical role for IL-10 in driving mucosal mast cell expansion and activation, suggesting that, in its absence, mast cell function is impaired, leading to attenuated food allergy symptoms. PMID:27183617

  3. The Role of TRP Proteins in Mast Cells

    PubMed Central

    Freichel, Marc; Almering, Julia; Tsvilovskyy, Volodymyr

    2012-01-01

    Transient receptor potential (TRP) proteins form cation channels that are regulated through strikingly diverse mechanisms including multiple cell surface receptors, changes in temperature, in pH and osmolarity, in cytosolic free Ca2+ concentration ([Ca2+]i), and by phosphoinositides which makes them polymodal sensors for fine tuning of many cellular and systemic processes in the body. The 28 TRP proteins identified in mammals are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. When activated, they contribute to cell depolarization and Ca2+ entry. In mast cells, the increase of [Ca2+]i is fundamental for their biological activity, and several entry pathways for Ca2+ and other cations were described including Ca2+ release activated Ca2+ (CRAC) channels. Like in other non-excitable cells, TRP channels could directly contribute to Ca2+ influx via the plasma membrane as constituents of Ca2+ conducting channel complexes or indirectly by shifting the membrane potential and regulation of the driving force for Ca2+ entry through independent Ca2+ entry channels. Here, we summarize the current knowledge about the expression of individual Trp genes with the majority of the 28 members being yet identified in different mast cell models, and we highlight mechanisms how they can regulate mast cell functions. Since specific agonists or blockers are still lacking for most members of the TRP family, studies to unravel their function and activation mode still rely on experiments using genetic approaches and transgenic animals. RNAi approaches suggest a functional role for TRPC1, TRPC5, and TRPM7 in mast cell derived cell lines or primary mast cells, and studies using Trp gene knock-out mice reveal a critical role for TRPM4 in mast cell activation and for mast cell mediated cutaneous anaphylaxis, whereas a direct role of cold- and menthol-activated TRPM8 channels seems to be unlikely for the development of cold urticaria at least in mice. PMID:22701456

  4. Canine oral mucosal mast cell tumours.

    PubMed

    Elliott, J W; Cripps, P; Blackwood, L; Berlato, D; Murphy, S; Grant, I A

    2016-03-01

    Mast cell tumours (MCTs) are the most common cutaneous tumours of dogs, however rarely they can arise from the oral mucosa. This subset of MCT is reported to demonstrate a more aggressive clinical course than those tumours on the haired skin and the authors hypothesised that dogs with oral, mucosal MCT would have a high incidence of local lymph node metastasis at presentation and that this would be a negative prognostic factor. An additional hypothesis was that mitotic index (MI) would be prognostic. This retrospective study examines 33 dogs with MCTs arising from the oral mucosa. The results suggest that oral mucosal MCTs in the dog have a high incidence of lymph node metastasis at diagnosis (55%) which results in a poor prognosis. MI and nodal metastasis is highly prognostic. Loco-regional progression is common in these patients and dogs with adequate local control of their tumour had an improved outcome. Despite a more aggressive clinical course, treatment can result in protracted survivals, even when metastasis is present. PMID:24215587

  5. Mast cells, brain inflammation and autism.

    PubMed

    Theoharides, Theoharis C; Stewart, Julia M; Panagiotidou, Smaro; Melamed, Isaac

    2016-05-01

    Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Mast cells (MCs) are located perivascularly close to neurons and microglia, primarily in the leptomeninges, thalamus, hypothalamus and especially the median eminence. Corticotropin-releasing factor (CRF) is secreted from the hypothalamus under stress and, together with neurotensin (NT), can stimulate brain MCs to release inflammatory and neurotoxic mediators that disrupt the blood-brain barrier (BBB), stimulate microglia and cause focal inflammation. CRF and NT synergistically stimulate MCs and increase vascular permeability; these peptides can also induce each other׳s surface receptors on MCs leading to autocrine and paracrine effects. As a result, brain MCs may be involved in the pathogenesis of "brain fog," headaches, and autism spectrum disorders (ASDs), which worsen with stress. CRF and NT are significantly increased in serum of ASD children compared to normotypic controls further strengthening their role in the pathogenesis of autism. There are no clinically affective treatments for the core symptoms of ASDs, but pilot clinical trials using natural-antioxidant and anti-inflammatory molecules reported statistically significant benefit. PMID:25941080

  6. Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma.

    PubMed

    Wang, Gang; Baines, Katherine J; Fu, Juan Juan; Wood, Lisa G; Simpson, Jodie L; McDonald, Vanessa M; Cowan, Douglas C; Taylor, D Robin; Cowan, Jan O; Gibson, Peter G

    2016-04-01

    Mast cells are a resident inflammatory cell of the airways, involved in both the innate and adaptive immune response. The relationship between mast cells and inflammatory phenotypes and treatment response of asthma is not clear.Clinical characteristics of subjects with stable asthma (n=55), inflammatory cell counts and gene expression microarrays in induced sputum were analysed. Sputum mast cell subtypes were determined by molecular phenotyping based on expression of mast cell biomarkers (tryptase (TPSAB1), chymase (CMA1) and carboxypeptidase A3 (CPA3)). Effects of mast cell subtypes on steroid response were observed in a prospective cohort study (n=50).MCT(n=18) and MCT/CPA3(mRNA expression of TPSAB1 and CPA3; n=29) subtypes were identified, as well as a group without mast cell gene expression (n=8). The MCT/CPA3 subtype had elevated exhaled nitric oxide fraction, sputum eosinophils, bronchial sensitivity and reactivity, and poorer asthma control. This was accompanied by upregulation of 13 genes. Multivariable logistic regression identified CPA3(OR 1.21, p=0.004) rather than TPSAB1(OR 0.92, p=0.502) as a determinant of eosinophilic asthma. The MCT/CPA3 subtype had a better clinical response and reduced signature gene expression with corticosteroid treatment.Sputum mast cell subtypes of asthma can be defined by a molecular phenotyping approach. The MCT/CPA3 subtype demonstrated increased bronchial sensitivity and reactivity, and signature gene expression, which was associated with airway eosinophilia and greater corticosteroid responsiveness. PMID:26699720

  7. Mast Cell Chemotaxis – Chemoattractants and Signaling Pathways

    PubMed Central

    Halova, Ivana; Draberova, Lubica; Draber, Petr

    2012-01-01

    Migration of mast cells is essential for their recruitment within target tissues where they play an important role in innate and adaptive immune responses. These processes rely on the ability of mast cells to recognize appropriate chemotactic stimuli and react to them by a chemotactic response. Another level of intercellular communication is attained by production of chemoattractants by activated mast cells, which results in accumulation of mast cells and other hematopoietic cells at the sites of inflammation. Mast cells express numerous surface receptors for various ligands with properties of potent chemoattractants. They include the stem cell factor (SCF) recognized by c-Kit, antigen, which binds to immunoglobulin E (IgE) anchored to the high affinity IgE receptor (FcεRI), highly cytokinergic (HC) IgE recognized by FcεRI, lipid mediator sphingosine-1-phosphate (S1P), which binds to G protein-coupled receptors (GPCRs). Other large groups of chemoattractants are eicosanoids [prostaglandin E2 and D2, leukotriene (LT) B4, LTD4, and LTC4, and others] and chemokines (CC, CXC, C, and CX3C), which also bind to various GPCRs. Further noteworthy chemoattractants are isoforms of transforming growth factor (TGF) β1–3, which are sensitively recognized by TGF-β serine/threonine type I and II β receptors, adenosine, C1q, C3a, and C5a components of the complement, 5-hydroxytryptamine, neuroendocrine peptide catestatin, tumor necrosis factor-α, and others. Here we discuss the major types of chemoattractants recognized by mast cells, their target receptors, as well as signaling pathways they utilize. We also briefly deal with methods used for studies of mast cell chemotaxis and with ways of how these studies profited from the results obtained in other cellular systems. PMID:22654878

  8. ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells

    PubMed Central

    Kapur, Reuben; Shi, Jianjian; Ghosh, Joydeep; Munugalavadla, Veerendra; Sims, Emily; Martin, Holly; Wei, Lei; Mali, Raghuveer Singh

    2016-01-01

    Understanding mast cell development is essential due to their critical role in regulating immunity and autoimmune diseases. Here, we show how Rho kinases (ROCK) regulate mast cell development and can function as therapeutic targets for treating allergic diseases. Rock1 deficiency results in delayed maturation of bone marrow derived mast cells (BMMCs) in response to IL-3 stimulation and reduced growth in response to stem cell factor (SCF) stimulation. Further, integrin-mediated adhesion and migration, and IgE-mediated degranulation are all impaired in Rock1-deficient BMMCs. To understand the mechanism behind altered mast cell development in Rock1−/− BMMCs, we analyzed the activation of ROCK and its downstream targets including LIM kinase (LIMK). We observed reduced activation of ROCK, LIMK, AKT and ERK1/2 in Rock1-deficient BMMCs in response to SCF stimulation. Further, loss of either Limk1 or Limk2 also demonstrated altered BMMC maturation and growth; combined deletion of both Limk1 and Limk2 resulted in further reduction in BMMC maturation and growth. In passive cutaneous anaphylaxis model, deficiency of Rock1 or treatment with ROCK inhibitor Fasudil protected mice against IgE-mediated challenge. Our results identify ROCK/LIMK pathway as a novel therapeutic target for treating allergic diseases involving mast cells. PMID:26943578

  9. Mast Cells as Cellular Sensors in Inflammation and Immunity

    PubMed Central

    Beghdadi, Walid; Madjene, Lydia Célia; Benhamou, Marc; Charles, Nicolas; Gautier, Gregory; Launay, Pierre; Blank, Ulrich

    2011-01-01

    Mast cells are localized in tissues. Intense research on these cells over the years has demonstrated their role as effector cells in the maintenance of tissue integrity following injury produced by infectious agents, toxins, metabolic states, etc. After stimulation they release a sophisticated array of inflammatory mediators, cytokines, and growth factors to orchestrate an inflammatory response. These mediators can directly initiate tissue responses on resident cells, but they have also been shown to regulate other infiltrating immune cell functions. Research in recent years has revealed that the outcome of mast cell actions is not always detrimental for the host but can also limit disease development. In addition, mast cell functions highly depend on the physiological context in the organism. Depending on the genetic background, strength of the injurious event, the particular microenvironment, mast cells direct responses ranging from pro- to anti-inflammatory. It appears that they have evolved as cellular sensors to discern their environment in order to initiate an appropriate physiological response either aimed to favor inflammation for repair or at the contrary limit the inflammatory process to prevent further damage. Like every sophisticated machinery, its dysregulation leads to pathology. Given the broad distribution of mast cells in tissues this also explains their implication in many inflammatory diseases. PMID:22566827

  10. Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model

    PubMed Central

    Nam, Gaewon; Jeong, Se Kyoo; Park, Bu Man; Lee, Sin Hee; Kim, Hyun Jong; Hong, Seung-Phil; Kim, Beomjoon

    2016-01-01

    Background Many inflammatory mediators, including various cytokines (e.g. interleukins and tumor necrosis factor [TNF]), inflammatory proteases, and histamine are released following mast cell activation. However, the endogenous modulators for mast cell activation and the underlying mechanism have yet to be elucidated. Endogenous cannabinoids such as palmitoylethanolamide (PEA) and N-arachidonoylethanolamine (anandamide or AEA), were found in peripheral tissues and have been proposed to possess autacoid activity, implying that cannabinoids may downregulate mast cell activation and local inflammation. Objective In order to investigate the effect of cannabinoid receptor-1 (CB1R) agonists on mast cell activation, AEA-derived compounds were newly synthesized and evaluated for their effect on mast cell activation. Methods The effects of selected compounds on FcεRI-induced histamine and β-hexosaminidase release were evaluated in a rat basophilic leukemia cell line (RBL-2H3). To further investigate the inhibitory effects of CB1R agonist in vivo, an oxazolone-induced atopic dermatitis mouse model was exploited. Results We found that CB1R inhibited the release of inflammatory mediators without causing cytotoxicity in RBL-2H3 cells and that CB1R agonists markedly and dose-dependently suppressed mast cell proliferation indicating that CB1R plays an important role in modulating antigen-dependent immunoglobulin E (IgE)-mediated mast cell activation. We also found that topical application of CB1R agonists suppressed the recruitment of mast cells into the skin and reduced the level of blood histamine. Conclusion Our results indicate that CB1R agonists down-regulate mast cell activation and may be used for relieving inflammatory symptoms mediated by mast cell activation, such as atopic dermatitis, psoriasis, and contact dermatitis. PMID:26848215

  11. Mast cell homeostasis and the JAK–STAT pathway

    PubMed Central

    Morales, JK; Falanga, YT; Depcrynski, A; Fernando, J; Ryan, JJ

    2011-01-01

    The Janus kinase/signal transducer and activator of transcription (JAK–STAT) pathway mediates important responses in immune cells. Activation of any of the four JAK family members leads to phosphorylation of one or more of seven STAT family members. Phosphorylation of STAT family members leads to their dimerization and translocation into the nucleus, in which they bind specific DNA sequences to activate gene transcription. Regulation of JAKs and STATs therefore has a significant effect on signal transduction and subsequent cellular responses. Mast cells are important mediators of allergic disease and asthma. These cells have the ability to cause profound inflammation and vasodilation upon the release of preformed mediators, as well as subsequent synthesis of new inflammatory mediators. The regulation of mast cells is therefore of intense interest for the treatment of allergic disease. An important regulator of mast cells, STAT5, is activated downstream of the receptors for immunoglobulin E, interleukin-3 and stem cell factor. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. Regulators of the JAK–STAT pathway, such as the suppressors of cytokine signaling (SOCS) and protein inhibitor of activated STAT (PIAS) proteins, are required to fine tune the immune response and maintain homeostasis. A better understanding of the role and regulation of JAKs and STATs in mast cells is vital for the development of new therapeutics. PMID:20535135

  12. Mast cell heterogeneity in non-human primates

    SciTech Connect

    Barrett, K.E.; Szucs, E.F.; Metcalfe, D.D.

    1986-03-05

    Mast cells of rodents may be subdivided in terms of their properties, but the extent of such heterogeneity in man and higher animals is still unknown. The authors have compared lung (LMC) and intestinal (IMC) mast cells obtained from individual monkeys. LMC contained more histamine (HA) than IMC (6.61+/-1.3 vs. 1.6+/-0.6 pg/cell, means+/-SEM, n=3). LMC released more HA (17.7+/-2.1% vs. 9.2+/-1.0%, means+/-SEM, n=16) and also generated more LTC/sub 4/ equivalents as measured by radioimmunoassay (range 13.4-41.5 vs. 3.0-4.0 ng/10/sup 6/ mast cells) following an anaphylactic stimulus. The majority (>90%) of LMC stained metachromatically under conditions appropriate for heparin-containing cells, whereas IMC required more forcing conditions to display metachromasia. In contrast to these quantitative and qualitative mediator differences, functional responses of LMC and IMC were similar. Thus, HA release was inhibited comparably by theophylline, isoprenaline and dibutyryl cyclic AMP, but quercetin was slightly more active on IMC. Substance P caused dose-related HA release from both cell types, although the amount released varied between individual animal, (range LMC 1.2-20.2%, IMC 1.8-23.0%, n=4). Other neuropeptides (pentagastrin) vasoactive intestinal peptide, neurotensin, somatostatin) did not release HA. They conclude that mast cell heterogeneity in higher animals may be reflected more by cytochemical rather than functional differences between mast cell classes.

  13. Mitochondrial calcium uniporter inhibition attenuates mouse bone marrow-derived mast cell degranulation induced by beta-1,3-glucan

    PubMed Central

    Cuong, Dang Van; Kim, Hyoung Kyu; Marquez, Jubert; Kim, Nari; Ko, Kyung Soo; Rhee, Byoung Doo

    2016-01-01

    Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular Ca2+, which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with 0.5 µg/ml BG, 100 µg/ml peptidoglycan (PGN), or 10 µM A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium-free conditions. Ruthenium red, a mitochondrial Ca2+ uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial Ca2+ uniporter has an important regulatory role in BG-induced mast cell degranulation. PMID:26937218

  14. Mitochondrial calcium uniporter inhibition attenuates mouse bone marrow-derived mast cell degranulation induced by beta-1,3-glucan.

    PubMed

    Cuong, Dang Van; Kim, Hyoung Kyu; Marquez, Jubert; Kim, Nari; Ko, Kyung Soo; Rhee, Byoung Doo; Han, Jin

    2016-03-01

    Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular Ca(2+), which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with 0.5 µg/ml BG, 100 µg/ml peptidoglycan (PGN), or 10 µM A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium-free conditions. Ruthenium red, a mitochondrial Ca(2+) uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial Ca(2+) uniporter has an important regulatory role in BG-induced mast cell degranulation. PMID:26937218

  15. Imaging immune response of skin mast cells in vivo with two-photon microscopy

    NASA Astrophysics Data System (ADS)

    Li, Chunqiang; Pastila, Riikka K.; Lin, Charles P.

    2012-02-01

    Intravital multiphoton microscopy has provided insightful information of the dynamic process of immune cells in vivo. However, the use of exogenous labeling agents limits its applications. There is no method to perform functional imaging of mast cells, a population of innate tissue-resident immune cells. Mast cells are widely recognized as the effector cells in allergy. Recently their roles as immunoregulatory cells in certain innate and adaptive immune responses are being actively investigated. Here we report in vivo mouse skin mast cells imaging with two-photon microscopy using endogenous tryptophan as the fluorophore. We studied the following processes. 1) Mast cells degranulation, the first step in the mast cell activation process in which the granules are released into peripheral tissue to trigger downstream reactions. 2) Mast cell reconstitution, a procedure commonly used to study mast cells functioning by comparing the data from wild type mice, mast cell-deficient mice, and mast-cell deficient mice reconstituted with bone marrow-derived mast cells (BMMCs). Imaging the BMMCs engraftment in tissue reveals the mast cells development and the efficiency of BMMCs reconstitution. We observed the reconstitution process for 6 weeks in the ear skin of mast cell-deficient Kit wsh/ w-sh mice by two-photon imaging. Our finding is the first instance of imaging mast cells in vivo with endogenous contrast.

  16. Mast cell degranulation – a mechanism for the anti-arrhythmic effect of endothelin-1?

    PubMed Central

    Walsh, SK; Kane, KA; Wainwright, CL

    2009-01-01

    Background and purpose: The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia. Experimental approach: Male Sprague-Dawley rats received either ET-1 (1.6 nmol·kg−1) in the presence or absence of disodium cromoglycate (DSCG; 20 mg·kg−1·h−1) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 µg·kg−1) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia. Key results: ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells. Conclusions and implications: These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation. PMID:19422371

  17. Utility of hydroxyurea in mast cell activation syndrome

    PubMed Central

    2013-01-01

    Mast cell activation syndrome (MCAS) is a relatively recently recognized cause of chronic multisystem polymorbidity of a generally inflammatory theme. Patients with MCAS often report migratory soft tissue and/or bone pain which frequently responds poorly to typical (narcotic and non-narcotic) analgesics as well as atypical analgesics such as antidepressants and anticonvulsants. Hydroxyurea (HU) is an oral ribonucleotide reductase inhibitor commonly used in the treatment of chronic myeloproliferative neoplasms and sickle cell anemia. HU has been used to treat systemic mastocytosis, sometimes effecting improvement in MC activation symptoms but not tumor burden, suggesting potential utility of the drug in MCAS, too. Reported here are five cases of successful use of relatively low-dose HU in MCAS to reduce symptoms including previously refractory soft tissue and/or bone pain. HU may be useful in treating mediator symptoms in MCAS, but further study is needed to define optimal dosing strategies and patient subpopulations most likely to benefit. PMID:24192267

  18. Inhibition of mast cell-dependent conversion of cultured macrophages into foam cells with antiallergic drugs.

    PubMed

    Ma, H; Kovanen, P T

    2000-12-01

    Degranulation of isolated, rat peritoneal mast cells in the presence of low density lipoprotein (LDL) induces cholesteryl ester accumulation in cocultured macrophages with ensuing foam cell formation. This event occurs when the macrophages phagocytose LDL particles that have been bound to the heparin proteoglycans of exocytosed granules. In an attempt to inhibit such foam cell formation pharmacologically, rat peritoneal mast cells that had been passively sensitized with anti-ovalbumin-IgE were treated with 2 mast cell-stabilizing antianaphylactic drugs, MY-1250 or disodium cromoglycate (DSCG). Both drugs were found to inhibit antigen (ovalbumin)-triggered release of histamine from the mast cells, revealing mast cell stabilization. In cocultures of rat peritoneal macrophages and passively sensitized mast cells, addition of MY-1250 before addition of the antigen resulted in parallel reductions in histamine release from mast cells, uptake of [(14)C]sucrose-LDL, and accumulation of LDL-derived cholesteryl esters in the cocultured macrophages. Similarly, when passively sensitized mast cells were stimulated with antigen in the presence of DSCG and the preconditioned media containing all substances released from the drug-treated mast cells were collected and added to macrophages cultured in LDL-containing medium, uptake and esterification of LDL cholesterol by the macrophages were inhibited. The inhibitory effects of both drugs were mast cell-specific because neither drug inhibited the ability of macrophages to take up and esterify LDL cholesterol. Analysis of heparin proteoglycan contents of the incubation media revealed that both drugs had inhibited mast cells from expelling their granule remnants. Thus, both MY-1250 and DSCG prevent mast cells from releasing the heparin proteoglycan-containing vehicles that bind LDL and carry it into macrophages. This study suggests that antiallergic pharmacological agents could be used in animal models to prevent mast cell

  19. Peritoneal mast cell stabilization potential of Pothos scandens L

    PubMed Central

    Gupta, Saurabh; Duraiswamy, B.; Satishkumar, M. N.

    2013-01-01

    Objective: To investigate the peritoneal mast cell stabilization activity of Pothos scandens extracts Materials and Methods: Pothos scandens L. (family- Araceae) aerial part was successively extracted with ethanol and aqueous to prepare extract of the plant. The extracts of P. scandens were evaluated for stabilization of mast cell in rat allergic models. The extract of P. scandens ethanolic, 50% aqueous ethanolic and aqueous (1, 10 and 100 μg/ml) was studied for peritoneal mast cell stabilization activity in rat mesenteric preparation induced by C 48/80. Result: Preliminary phytochemical analysis revealed the presence of carbohydrates, fixed oil, proteins, alkaloids, glycosides, flavonoids and phenolic compounds. The ethanolic, 50% aqueous ethanolic and aqueous extracts of P. scandens L. showed dose dependent increase in the number of intact cells when compare with C48/80 at the concentration of 10 and 100 μg/ml. It virtues further work towards the isolation of phytoconstituents from this plant. Conclusion: This finding provides evidence that the P. scandens L. inhibits mast cell-derived immediate-type allergic reactions and mast cell degranulation. P. scandens has a potential as allergic anti- asthmatic agent. PMID:23542883

  20. Effect of methylmercury on the rat mast cell degranulation

    NASA Astrophysics Data System (ADS)

    Graevskaya, E. E.; Yasutake, A.; Aramai, R.; Rubin, A. B.

    2003-05-01

    Methylmercury is the well-known neurotoxicant as weil as a modulator of the immune system. We investigated the effects of MeHg on the rat mast cell degranulation induced by nonimmunological stimuli (the selective liberator of histamine, compound 48/80, and calcium ionophore A23187) both in vivo and in vitro. In 8, 12 and 15 days afterthe final administration of MeHg we observed the suppression of calcium ionophore A23187-and 48/80-induced histamine release, which enhanced with time. In experiments in vitro incubation of peritoneal mast cells with MeHg alone in the dose range 10^{-8} to 10^{-6} did not induce mast cell degranulation, however modified the activation of mast cells by compound 48/80, and calcium ionophore A23187. We observed activation of stimulated secretion by preliminary incubation with low dose of MeHg 10^{-8} M and inhibition by dose of MeHg 10^{-6} M. These results show that MeHg treatment can modify mast cell function in vivo and in vitro and provide insight into the understanding what role this cell has in the pathogenesis of Minamata disease-comlected disorders.

  1. Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

    PubMed Central

    Galli, Stephen J.; Tsai, Mindy; Marichal, Thomas; Tchougounova, Elena; Reber, Laurent L.; Pejler, Gunnar

    2016-01-01

    The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such “controversial” results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified. PMID:25727288

  2. Phenotypic variability in human skin mast cells.

    PubMed

    Babina, Magda; Guhl, Sven; Artuc, Metin; Trivedi, Neil N; Zuberbier, Torsten

    2016-06-01

    Mast cells (MCs) are unique constituents of the human body. While inter-individual differences may influence the ways by which MCs operate in their skin habitat, they have not been surveyed in a comprehensive manner so far. We therefore set out to quantify skin MC variability in a large cohort of subjects. Pathophysiologically relevant key features were quantified and correlated: transcripts of c-kit, FcεRIα, FcεRIβ, FcεRIγ, histidine decarboxylase, tryptase, and chymase; surface expression of c-Kit, FcεRIα; activity of tryptase, and chymase; histamine content and release triggered by FcεRI and Ca(2+) ionophore. While there was substantial variability among subjects, it strongly depended on the feature under study (coefficient of variation 33-386%). Surface expression of FcεRI was positively associated with FcεRIα mRNA content, histamine content with HDC mRNA, and chymase activity with chymase mRNA. Also, MC signature genes were co-regulated in distinct patterns. Intriguingly, histamine levels were positively linked to tryptase and chymase activity, whereas tryptase and chymase activity appeared to be uncorrelated. FcεRI triggered histamine release was highly variable and was unrelated to FcεRI expression but unexpectedly tightly correlated with histamine release elicited by Ca(2+) ionophore. This most comprehensive and systematic work of its kind provides not only detailed insights into inter-individual variability in MCs, but also uncovers unexpected patterns of co-regulation among signature attributes of the lineage. Differences in MCs among humans may well underlie clinical responses in settings of allergic reactions and complex skin disorders alike. PMID:26706922

  3. Expression profiling of constitutive mast cells reveals a unique identity within the immune system.

    PubMed

    Dwyer, Daniel F; Barrett, Nora A; Austen, K Frank

    2016-07-01

    Mast cells are evolutionarily ancient sentinel cells. Like basophils, mast cells express the high-affinity receptor for immunoglobulin E (IgE) and have been linked to host defense and diverse immune-system-mediated diseases. To better characterize the function of these cells, we assessed the transcriptional profiles of mast cells isolated from peripheral connective tissues and basophils isolated from spleen and blood. We found that mast cells were transcriptionally distinct, clustering independently from all other profiled cells, and that mast cells demonstrated considerably greater heterogeneity across tissues than previously appreciated. We observed minimal homology between mast cells and basophils, which shared more overlap with other circulating granulocytes than with mast cells. The derivation of mast-cell and basophil transcriptional signatures underscores their differential capacities to detect environmental signals and influence the inflammatory milieu. PMID:27135604

  4. Atherosclerosis: a chronic inflammatory disease mediated by mast cells.

    PubMed

    Conti, Pio; Shaik-Dasthagirisaeb, Yazdami

    2015-01-01

    Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells. PMID:26648785

  5. Atherosclerosis: a chronic inflammatory disease mediated by mast cells

    PubMed Central

    Shaik-Dasthagirisaeb, Yazdami

    2015-01-01

    Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells. PMID:26648785

  6. Mast cell tryptases and chymases in inflammation and host defense

    PubMed Central

    Caughey, George H.

    2008-01-01

    Summary Tryptases and chymases are the major proteins stored and secreted by mast cells. The types, amounts and properties of these serine peptidases vary by mast cell subtype, tissue, and mammal of origin. Membrane-anchored γ-tryptases are tryptic, prostasin-like, type I peptidases that remain membrane-attached upon release and act locally. Soluble tryptases, including their close relatives, mastins, form inhibitor-resistant oligomers that act more remotely. Befitting their greater destructive potential, chymases are quickly inhibited after release, although some gain protection by associating with proteoglycans. Most chymase-like enzymes, including mast cell cathepsin G, hydrolyze chymotryptic substrates, an uncommon capability in the proteome. Some rodent chymases, however, have mutations resulting in elastolytic activity. Secreted tryptases and chymases promote inflammation, matrix destruction, and tissue remodeling by several mechanisms, including destroying pro-coagulant, matrix, growth and differentiation factors, and activating proteinase-activated receptors, urokinase, metalloproteinases, and angiotensin. They also modulate immune responses by hydrolyzing chemokines and cytokines. At least one chymase protects mice from intestinal worms. Tryptases and chymases also can oppose inflammation by inactivating allergens and neuropeptides causing inflammation and bronchoconstriction. Thus, like mast cells themselves, mast cell serine peptidases play multiple roles in host defense and any accounting of benefit versus harm is necessarily context-specific. PMID:17498057

  7. Mast cell-cholinergic nerve interaction in mouse airways.

    PubMed

    Weigand, Letitia A; Myers, Allen C; Meeker, Sonya; Undem, Bradley J

    2009-07-01

    We addressed the mechanism by which antigen contracts trachea isolated from actively sensitized mice. Trachea were isolated from mice (C57BL/6J) that had been actively sensitized to ovalbumin (OVA). OVA (10 microg ml(-1)) caused histamine release (approximately total tissue content), and smooth muscle contraction that was rapid in onset and short-lived (t(1/2) < 1 min), reaching approximately 25% of the maximum tissue response. OVA contraction was mimicked by 5-HT, and responses to both OVA and 5-HT were sensitive to 10 microm-ketanserin (5-HT(2) receptor antagonist) and strongly inhibited by atropine (1microm). Epithelial denudation had no effect on the OVA-induced contraction. Histological assessment revealed about five mast cells/tracheal section the vast majority of which contained 5-HT. There were virtually no mast cells in the mast cell-deficient (sash -/-) mouse trachea. OVA failed to elicit histamine release or contractile responses in trachea isolated from sensitized mast cell-deficient (sash -/-) mice. Intracellular recordings of the membrane potential of parasympathetic neurons in mouse tracheal ganglia revealed a ketanserin-sensitive 5-HT-induced depolarization and similar depolarization in response to OVA challenge. These data support the hypothesis that antigen-induced contraction of mouse trachea is epithelium-independent, and requires mast cell-derived 5-HT to activate 5-HT(2) receptors on parasympathetic cholinergic neurons. This leads to acetylcholine release from nerve terminals, and airway smooth muscle contraction. PMID:19403609

  8. Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia

    PubMed Central

    McKittrick, Craig M; Lawrence, Catherine E; Carswell, Hilary V O

    2015-01-01

    Blood brain barrier (BBB) breakdown and neuroinflammation are key events in ischemic stroke morbidity and mortality. The present study investigated the effects of mast cell deficiency and stabilization on BBB breakdown and neutrophil infiltration in mice after transient middle cerebral artery occlusion (tMCAo). Adult male C57BL6/J wild type (WT) and mast cell-deficient (C57BL6/J KitWsh/Wsh (Wsh)) mice underwent tMCAo and BBB breakdown, brain edema and neutrophil infiltration were examined after 4 hours of reperfusion. Blood brain barrier breakdown, brain edema, and neutrophil infiltration were significantly reduced in Wsh versus WT mice (P<0.05). These results were reproduced pharmacologically using mast cell stabilizer, cromoglycate. Wild-type mice administered cromoglycate intraventricularly exhibited reduced BBB breakdown, brain edema, and neutrophil infiltration versus vehicle (P<0.05). There was no effect of cromoglycate versus vehicle in Wsh mice, validating specificity of cromoglycate on brain mast cells. Proteomic analysis in Wsh versus WT indicated that effects may be via expression of endoglin, endothelin-1, and matrix metalloproteinase-9. Using an in vivo model of mast cell deficiency, this is the first study showing that mast cells promote BBB breakdown in focal ischemia in mice, and opens up future opportunities for using mice to identify specific mechanisms of mast cell-related BBB injury. PMID:25564235

  9. Meningeal mast cell-T cell crosstalk regulates T cell encephalitogenicity.

    PubMed

    Russi, Abigail E; Walker-Caulfield, Margaret E; Guo, Yong; Lucchinetti, Claudia F; Brown, Melissa A

    2016-09-01

    GM-CSF is a cytokine produced by T helper (Th) cells that plays an essential role in orchestrating neuroinflammation in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. Yet where and how Th cells acquire GM-CSF expression is unknown. In this study we identify mast cells in the meninges, tripartite tissues surrounding the brain and spinal cord, as important contributors to antigen-specific Th cell accumulation and GM-CSF expression. In the absence of mast cells, Th cells do not accumulate in the meninges nor produce GM-CSF. Mast cell-T cell co-culture experiments and selective mast cell reconstitution of the meninges of mast cell-deficient mice reveal that resident meningeal mast cells are an early source of caspase-1-dependent IL-1β that licenses Th cells to produce GM-CSF and become encephalitogenic. We also provide evidence of mast cell-T cell co-localization in the meninges and CNS of recently diagnosed acute MS patients indicating similar interactions may occur in human demyelinating disease. PMID:27396526

  10. Critical Role for Mast Cell Stat5 Activity in Skin Inflammation

    PubMed Central

    Ando, Tomoaki; Xiao, Wenbin; Gao, Peisong; Namiranian, Siavash; Matsumoto, Kenji; Tomimori, Yoshiaki; Hong, Hong; Yamashita, Hirotaka; Kimura, Miho; Kashiwakura, Jun-ichi; Hata, Tissa R.; Izuhara, Kenji; Gurish, Michael F.; Roers, Axel; Rafaels, Nicholas M.; Barnes, Kathleen C.; Jamora, Colin; Kawakami, Yuko; Kawakami, Toshiaki

    2015-01-01

    SUMMARY Atopic dermatitis (AD) is a chronic inflammatory skin disease. Here, we show that phospholipase C-β3 (PLC-β3)-deficient mice spontaneously develop AD-like skin lesions and more severe allergen-induced dermatitis than wild-type mice. Mast cells were required for both AD models and remarkably increased in the skin of Plcb3−/− mice because of the increased Stat5 and reduced SHP-1 activities. Mast cell-specific deletion of Stat5 gene ameliorated allergen-induced dermatitis, whereas that of Shp1 gene encoding Stat5-inactivating SHP-1 exacerbated it. PLC-β3 regulates the expression of periostin in fibroblasts and TSLP in keratinocytes, two proteins critically involved in AD pathogenesis. Furthermore, polymorphisms in PLCB3, SHP1, STAT5A, and STAT5B genes were associated with human AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels of phospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis. PMID:24412367

  11. Effect of disodium cromoglycate on mast cell-mediated immediate-type allergic reactions.

    PubMed

    Shin, Hye-Young; Kim, Jung-Sook; An, Nyeon-Hyoung; Park, Rae-Kil; Kim, Hyung-Min

    2004-04-23

    We investigated the effect of disodium cromoglycate (DSCG) on mast cell-mediated immediate-type hypersensitivity. DSCG inhibited systemic allergic reaction induced by compound 48/80 dose-dependently. Passive cutaneous anaphylaxis was inhibited by 71.6% by oral administration of DSCG (1 g/kg). When DSCG was pretreated at concentration rang from 0.01-1000 g/kg, the serum histamine levels were reduced in a dose dependent manner. DSCG also significantly inhibited histamine release from rat peritoneal mast cell (RPMC) by compound 48/80. We confirmed that DSCG inhibited compound 48/80-induced degranulation of RPMC by alcian blue/nuclear fast red staining. In addition, DSCG showed a significant inhibitory effect on anti-dinitrophenyl IgE-mediated tumor necrosis factor-alpha production. These results indicate that DSCG inhibits mast cell-mediated immediate-type allergic reaction. PMID:15050425

  12. Human mast cell chymase induces the accumulation of neutrophils, eosinophils and other inflammatory cells in vivo

    PubMed Central

    He, Shaoheng; Walls, Andrew F

    1998-01-01

    The roles of chymase in acute allergic responses are not clear, despite the relative abundance of this serine proteinase in the secretory granules of human mast cells. We have isolated chymase to high purity from human skin tissue by heparin-agarose affinity chromatography and Sephacryl S-200 gel filtration procedures, and have investigated the ability of human mast cell chymase to stimulate cell accumulation following injection into laboratory animals.Injection of chymase provoked marked neutrophilia and eosinophilia in the skin of Dunkin Hartley guinea-pigs. Compared with saline injected control animals, there were some 60 fold more neutrophils and 12 fold more eosinophils present at the injection site.Following injection of chymase into the peritoneum of BALB/c mice, there were up to 700 fold more neutrophils, 21 fold more eosinophils, 19 fold more lymphocytes and 7 fold more macrophages recovered than from saline injected controls at 16 h. Doses of chymase as low as 5 ng (1.7×10−13 mole) stimulated an inflammatory infiltrate, and significant neutrophilia was elicited within 3 h.The chymase induced cell accumulation in both the guinea-pig and mouse models was dependent on an intact catalytic site, being reduced by co-injection of proteinase inhibitors or heat inactivation of the enzyme.Co-injection of histamine or heparin significantly reduced the chymase induced neutrophil accumulation, whereas neither histamine nor heparin by themselves had any effect on the accumulation of nucleated cells. No synergistic or antagonist interactions between chymase and tryptase were observed when these two major mast cell proteinases were co-injected into the mouse peritoneum.Our findings suggest that chymase may provide an potent stimulus for inflammatory cell recruitment following mast cell activation. PMID:9884078

  13. Mast cells, glia and neuroinflammation: partners in crime?

    PubMed Central

    Skaper, Stephen D; Facci, Laura; Giusti, Pietro

    2014-01-01

    Glia and microglia in particular elaborate pro-inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro-inflammatory signals released from other non-neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood–spinal cord and blood–brain barriers when barrier compromise results from CNS pathology. Growing evidence of mast cell–glia communication opens new perspectives for the development of therapies targeting neuroinflammation by differentially modulating activation of non-neuronal cells that normally control neuronal sensitization – both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be up-regulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamine family. One such member, N-palmitoylethanolamine is proposed to have a key role in maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N-Palmitoylethanolamine has proven efficacious in mast-cell-mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell–microglia cross-talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings. PMID:24032675

  14. Ultrastructural similarity between bat and human mast cell secretory granules.

    PubMed

    Oliani, S M; Vugman, I; Jamur, M C

    1993-01-01

    Mast cells in the tongue of the bat (Artibeus lituratus) show a well-developed Golgi area and abundant mitochondria in the granule-free perinuclear cytoplasm. Rough endoplasmic reticulum profiles, free ribosomes, mitochondria, bundles of filaments and a great number of secretory granules are found throughout the remaining cytoplasm. The granules, of various shapes and sizes, are simple containing an electron-dense, homogeneous matrix, coarse particles or cylindrical scrolls, or combinations (cylindrical scrolls with either electron-dense, homogeneous matrix or coarse particle contents). Up to now, scroll-containing granules have been considered to be a unique feature of human mast cells. PMID:8453310

  15. An essential role for mast cells as modulators of neutrophils influx in collagen-induced arthritis in the mouse

    PubMed Central

    Pimentel, Tatiana Aparecida; Sampaio, Andrxsé Luiz Franco; D’Acquisto, Fulvio; Perretti, Mauro; Oliani, Sonia Maria

    2012-01-01

    Mast cells are involved in immune disorders so that many of the proinflammatory and tissue destructive mediators produced by these cells have been implicated in the pathogenesis of rheumatoid arthritis. This scenario prompted us to investigate the correlation between mast cell degranulation and neutrophil influx within the digits and knees joints of arthritic mice assessing what could be the functional role(s) of joint mast cells in the response to collagen immunization. DBA/1J mice were submitted to collagen-induced arthritis and disease was assessed on day 21, 32 and 42 post-immunization. Pharmacological treatment with the glucocorticoid prednisolone, commonly used in the clinic, and nedocromil, a mast cell stabilizer, was performed from day 21 to 30. Arthritis developing after immunization gradually increased up to day 42. Neutrophil infiltration peaked on day 32 and 21, in the digits and knees, respectively, showing an unequal pattern of recruitment between these tissues. This difference emerged for mast cell they peaked in the digits on day 21, but a higher degree of degranulation could be measured in the knee joints. Uneven modulation of arthritis occurred after treatment of mice with prednisolone or nedocromil. Neutrophils migration to the tissue was reduced after both therapies, but only prednisolone augmented mast cell migration to the joints. Nedocromil exerted inhibitory properties both on mast cell proliferation and migration, more effectively on the digit joints. Thus, collagen induced an inflammatory process characterized by tissue mast cells activation and degranulation, suggesting a potential driving force in propagating inflammatory circuits yielding recruitment of neutrophils. However, the different degree of affected joint involvement suggests a time-related implication of digits and knees during collagen-induced arthritis development. These results provide evidence for local alterations whereby mast cells contribute to the initiation of

  16. Murine Mast Cells Secrete and Respond to Interleukin-33

    PubMed Central

    Tung, Hui-Ying; Plunkett, Beverly; Huang, Shau-Ku

    2014-01-01

    Interleukin-33 (IL-33) appears to play a crucial role in the expression of allergic diseases, but its cellular source and regulatory mechanisms remain to be fully elucidated. Mast cells, one of the major effecter cell populations in mediating allergy, express high levels of IL-33 receptor, ST2, and have been shown to express IL-33 transcripts. In this study, we aimed to examine the secretion of IL-33 in mast cells and their response to IL-33. We have successfully detected secreted IL-33 from cell supernatants through a modified enzyme-linked immunosorbent assay (ELISA) technique—cell-based ELISA. Activation of bone marrow-derived cultured mast cells (BMMCs) by crosslinkage of an antigen [ovalbumin (OVA)] and OVA-specific IgE mAbs significantly induced the expression of IL-33 transcripts, cytosolic and secreted proteins. In addition, the Toll-like receptor (TLR) 2 and TLR-9 ligands could trigger IL-33 mRNA expression. Exposure of BMMCs to IL-33 significantly increased the levels of IL-13 and IL-6 expression, concomitant with enhanced activation of mitogen-activated protein kinase (MAPKs) (ERK, p38, and JNK) and nuclear factor-kappa B. These results suggest that mouse BMMCs are capable of producing and serving as endogenous sources of IL-33, and that IL-33 plays an important role in regulating mast cell functions. PMID:24028396

  17. Lin− CD34hi CD117int/hi FcεRI+ cells in human blood constitute a rare population of mast cell progenitors

    PubMed Central

    Dahlin, Joakim S.; Malinovschi, Andrei; Öhrvik, Helena; Sandelin, Martin; Janson, Christer; Alving, Kjell

    2016-01-01

    Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow–derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34+ progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage-negative (Lin−) CD34hi CD117int/hi FcεRI+ progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin β7 and developed a mast cell–like phenotype, although with a slow cell division capacity in vitro. Isolated Lin− CD34hi CD117int/hi FcεRI+ blood cells had an immature mast cell–like appearance and expressed high levels of many mast cell–related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A messenger RNA transcripts were detected by quantitative reverse transcription–polymerase chain reaction. Altogether, we propose that the Lin− CD34hi CD117int/hi FcεRI+ blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of Lin− CD34hi CD117int/hi FcεRI+ blood mast cell progenitors than asthmatics with normal lung function. PMID:26626992

  18. n-3 Polyunsaturated fatty acids inhibit Fc ε receptor I-mediated mast cell activation.

    PubMed

    Wang, Xiaofeng; Ma, David W L; Kang, Jing X; Kulka, Marianna

    2015-12-01

    In vivo models show that n-3 polyunsaturated fatty acids (PUFA) inhibit some of the processes associated with allergic inflammation but the direct effect of n-3 PUFA on mast cells, the major effector cells in allergy, is poorly understood. We sought to determine the effect and mechanism of n-3 PUFA on Fc ε receptor I (FcεRI)-mediated signal transduction and mast cell activation. Bone marrow-derived mast cells (BMMC) were differentiated from bone marrow obtained from C57BL/6 wild-type (WT) and fat-1 transgenic mice. The fat-1 mice express fatty acid n-3 desaturase and produce endogenous n-3 PUFA. For comparison, exogenous n-3 PUFA were supplemented to WT BMMC and human mast cell (LAD2) cultures. Fat-1 BMMC released less β-hexosaminidase (β-hex) and cysteinyl leukotrienes and produced less tumor necrosis factor and chemokine (C-C motif) ligand 2. n-3 PUFA supplementation reduced LAD2 and BMMC degranulation (β-hex release) following FcεRI activation. Fat-1 BMMC expressed less constitutive Lyn and linker of activated T cells (LAT), and FcεRI-mediated phosphorylation of Lyn, spleen tyrosine kinase and LAT were reduced in fat-1 BMMC. Although the expression of surface and whole cell FcεRI was similar in WT and fat-1 BMMC, unstimulated fat-1 BMMC showed reduced FcεRI localization to lipid rafts, and stimulation with antigen resulted in aberrant FcεRI shuttling to the rafts. Our results show that n-3 PUFA suppress FcεRI-mediated activation of mast cells, which results in reduced mediator release. This effect is associated with a decrease in LAT and Lyn expression as well as abnormal shuttling of FcεRI to lipid rafts. PMID:26363927

  19. Mast cells: Versatile regulators of inflammation, tissue remodeling, host defense and homeostasis

    PubMed Central

    Galli, Stephen J.; Tsai, Mindy

    2009-01-01

    Summary The possible roles of mast cells in heath and disease have been a topic of interest for over one hundred and twenty five years. Many adaptive or pathological processes affecting the skin or other anatomical sites have been associated with morphological evidence of mast cell activation, and/or with changes in mast cell numbers or phenotype. Such observations, taken together with the known functions of the diverse mediators, cytokines and growth factors which can be secreted by mast cells, have suggested many potential functions for mast cells in health and disease. Definitively identifying the importance of mast cells in biological responses in humans is difficult. However, mutant mice which are profoundly mast cell-deficient, especially those which can undergo engraftment with wild type or genetically-altered mast cells, provide an opportunity to investigate the importance of mast cells, and specific mast cell functions or products, in various adaptive or pathological responses in mice. Such work has shown that mast cells can significantly influence multiple features of inflammatory or immune responses, through diverse effects that can either promote or, surprisingly, suppress, aspects of these responses. Through such functions, mast cells can significantly influence inflammation, tissue remodeling, host defense and homeostasis. PMID:18024086

  20. Mast Cell Targeted Chimeric Toxin Can Be Developed as an Adjunctive Therapy in Colon Cancer Treatment

    PubMed Central

    Wang, Shan; Li, Linmei; Shi, Renren; Liu, Xueting; Zhang, Junyan; Zou, Zehong; Hao, Zhuofang; Tao, Ailin

    2016-01-01

    The association of colitis with colorectal cancer has become increasingly clear with mast cells being identified as important inflammatory cells in the process. In view of the relationship between mast cells and cancer, we studied the effect and mechanisms of mast cells in the development of colon cancer. Functional and mechanistic insights were gained from ex vivo and in vivo studies of cell interactions between mast cells and CT26 cells. Further evidence was reversely obtained in studies of mast cell targeted Fcε-PE40 chimeric toxin. Experiments revealed mast cells could induce colon tumor cell proliferation and invasion. Cancer progression was found to be related to the density of mast cells in colonic submucosa. The activation of MAPK, Rho-GTPase, and STAT pathways in colon cancer cells was triggered by mast cells during cell-to-cell interaction. Lastly, using an Fcε-PE40 chimeric toxin we constructed, we confirmed the promoting effect of mast cells in development of colon cancer. Mast cells are a promoting factor of colon cancer and thus also a potential therapeutic target. The Fcε-PE40 chimeric toxin targeting mast cells could effectively prevent colon cancer in vitro and in vivo. Consequently, these data may demonstrate a novel immunotherapeutic approach for the treatment of tumors. PMID:26978404

  1. Cutaneous mast cell tumor (Mastocytoma): Cyto- histopathological and haematological investigations

    PubMed Central

    2014-01-01

    Cutaneous mast cell tumours (MCTs) are the most common skin tumours in dogs. Due to the prevalence of canine MCTs and the variable biologic behavior of this disease, accurate prognostication and a thorough understanding of MCT biology are critical for the treatment of this disease. A cytologic diagnosis of mast cell tumor with evidence of prior hemorrhage was made, and the masses were surgically removed. Cytological evaluation of fine-needle aspirates from the cutaneous mass from the axillary comprised many well-differentiated, highly granulated mast cells with moderate numbers of eosinophils. Nuclei were varied in size and shape with high nuclear’to’cytoplasmic ratio, prominent nucleoli, marked atypical and mitotic figures. Microscopically, mass consisted of sheets of neoplastic round cells that formed nonencapsulated nodules in the dermis and infiltrated into the adjacent dermal collagen, and also there was diffuse subcutis invasion of round to pleomorphic tumor cells. Tumor cells had moderate to abundant cytoplasm, round to ovoid nuclei with scattered chromatin, and mitotic figures. In this tumor, cytoplasmic granules showed atypical metachromasia. In addition, eosinophils were scattered among the mast cells at the periphery of the nodules. The presence of eosinophils and the observation, at high magnification, of cells with cytoplasmic metachromatic granules. Invasion of the deep subcutaneous fat or cutaneous muscles were a common feature of grade III tumour. Finally, a diagnosis of grade III cutaneous mast cell tumor was made. Virtual slides The virtual slide(s) of this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4755249151157024. PMID:24444100

  2. Mast cells mediate the immune suppression induced by dermal exposure to JP-8 jet fuel.

    PubMed

    Limón-Flores, Alberto Y; Chacón-Salinas, Rommel; Ramos, Gerardo; Ullrich, Stephen E

    2009-11-01

    Applying jet propulsion-8 (JP-8) jet fuel to the skin of mice induces immune suppression. Applying JP-8 to the skin of mice suppresses T-cell-mediated immune reactions including, contact hypersensitivity (CHS) delayed-type hypersensitivity and T-cell proliferation. Because dermal mast cells play an important immune regulatory role in vivo, we tested the hypothesis that mast cells mediate jet fuel-induced immune suppression. When we applied JP-8 to the skin of mast cell deficient mice CHS was not suppressed. Reconstituting mast cell deficient mice with wild-type bone marrow derived mast cells (mast cell "knock-in mice") restored JP-8-induced immune suppression. When, however, mast cells from prostaglandin E(2) (PGE(2))-deficient mice were used, the ability of JP-8 to suppress CHS was not restored, indicating that mast cell-derived PGE(2) was activating immune suppression. Examining the density of mast cells in the skin and lymph nodes of JP-8-treated mice indicated that jet fuel treatment caused an initial increase in mast cell density in the skin, followed by increased numbers of mast cells in the subcutaneous space and then in draining lymph nodes. Applying JP-8 to the skin increased mast cell expression of CXCR4, and increased the expression of CXCL12 by draining lymph node cells. Because CXCL12 is a chemoattractant for CXCR4+ mast cells, we treated JP-8-treated mice with AMD3100, a CXCR4 antagonist. AMD3100 blocked the mobilization of mast cells to the draining lymph node and inhibited JP-8-induced immune suppression. Our findings demonstrate the importance of mast cells in mediating jet fuel-induced immune suppression. PMID:19726579

  3. Phenotypic characterization of stem cell factor-dependent human foetal liver-derived mast cells.

    PubMed Central

    Nilsson, G; Forsberg, K; Bodger, M P; Ashman, L K; Zsebo, K M; Ishizaka, T; Irani, A M; Schwartz, L B

    1993-01-01

    Human foetal liver cells are an enriched source of mast cell progenitors that complete their differentiation and mature in response to stem cell factor, the ligand for Kit, in liquid culture. These mast cells are Kit+, metachromatic with toluidine blue+, tryptase+, histamine+ and show ultrastructure features of mast cells. Using a panel of monoclonal antibodies (mAb) against different cell-surface antigens (33 mAb were used), the cell-surface phenotype of human stem cell factor-dependent foetal liver-derived mast cells was examined by flow cytometry. Consistent with previous reports on tissue-derived mast cells, those derived from foetal liver in vitro expressed HLA class I, CD9, CD29, CD33, CD43, CD45 and Kit. Unlike mast cells dispersed from tissue, a high expression of CD13 was found. Also, these in vitro-derived mast cells express little, if any, high-affinity IgE receptor. However, small amounts of mRNA for the alpha-chain in foetal liver-derived mast cells compared to KU812 cells (a human basophil-like cell line) could be detected by Northern blotting. Full expression of Fc epsilon RI may require additional growth factor(s). Images Figure 2 PMID:7688344

  4. Mast cell degranulation activates a pain pathway underlying migraine headache

    PubMed Central

    Levy, Dan; Burstein, Rami; Kainz, Vanessa; Jakubowski, Moshe; Strassman, Andrew M.

    2007-01-01

    Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell - induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine. PMID:17459586

  5. Mast Cell-Nerve Cell Interaction at Acupoint: Modeling Mechanotransduction Pathway Induced by Acupuncture

    PubMed Central

    Yao, Wei; Yang, Hongwei; Yin, Na; Ding, Guanghong

    2014-01-01

    Mast cells are found abundant at sites of acupoints. Nerve cells share perivascular localization with mast cells. Acupuncture (mechanical stimuli) can activate mast cells to release adenosine triphosphate (ATP) which can activate nerve cells and modulates pain-processing pathways in response to acupuncture. In this paper, a mathematical model was constructed for describing intracellular Ca2+ signal and ATP release in a coupled mast cell and nerve cell system induced by mechanical stimuli. The results showed mechanical stimuli lead to a intracellular Ca2+ rise in the mast cell and ATP release, ATP diffuses in the extracellular space (ECS) and activates the nearby nerve cells, then induces electrical current in the nerve cell which spreads in the neural network. This study may facilitate our understanding of the mechanotransduction process induced by acupuncture and provide a methodology for quantitatively analyzing acupuncture treatment. PMID:24910530

  6. Characterization of redox activity in resting and activated mast cells by reduction and reoxidation of lipophilic nitroxides.

    PubMed

    Suzuki-Nishimura, T; Swartz, H M

    1998-10-01

    1. We measured redox systems in resting and activated rat peritoneal mast cells under anoxia by using the redox metabolism of free doxyl stearic acid (5DS) and phosphatidylcholine with two 5DS molecules esterified to the glycerol (di5DSPC). 2. In the absence of oxygen, 5DS and di5DSPC were reduced to the corresponding hydroxylamines by resting mast cells, with apparent first-order kinetics of 0.085 and 0.078/min, respectively. 3. The activation of mast cells induced by compound 48/80 and bradykinin did not affect the rates of reduction of the nitroxides, and therefore the activation appeared not to be closely coupled to the redox system of these cells; this finding implies that ischemia is unlikely to affect histamine release from mast cells. 4. The oxidation of the nitroxides by the mast cells was very fast and may be nonenzymatic. 5. We concluded that nitroxides can be useful probes of redox metabolism in the mast cells but, because the characteristics of the cellular reduction-reoxidation systems differed from that of other cells, the use of this approach in other cells will require careful characterization of the redox metabolism of nitroxides in those cells. PMID:9792226

  7. Diagnosis and treatment of mast cell disorders: practical recommendations.

    PubMed

    Sandes, Alex Freire; Medeiros, Raphael Salles Scortegagna; Rizzatti, Edgar Gil

    2013-01-01

    CONTEXT AND OBJECTIVE The term mastocytosis covers a group of rare disorders characterized by neoplastic proliferation and accumulation of clonal mast cells in one or more organs. The aim of this study was to assess the principal elements for diagnosing and treating these disorders. DESIGN AND SETTING Narrative review of the literature conducted at Grupo Fleury, São Paulo, Brazil. METHODS This study reviewed the scientific papers published in the PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde) and Cochrane Library databases that were identified using the search term "mastocytosis." RESULTS The clinical presentation of mastocytosis is remarkably heterogeneous and ranges from skin lesions that may regress spontaneously to aggressive forms associated with organ failure and short survival. Currently, seven subtypes of mastocytosis are recognized through the World Health Organization classification system for hematopoietic tumors. These disorders are diagnosed based on clinical manifestations and on identification of neoplastic mast cells using morphological, immunophenotypic, genetic and molecular methods. Abnormal mast cells display atypical and frequently spindle-shaped morphology, and aberrant expression of the CD25 and CD2 antigens. Elevation of serum tryptase is a common finding in some subtypes, and more than 90% of the patients present the D816V KIT mutation in mast cells. CONCLUSION Here, we described the most common signs and symptoms among patients with mastocytosis and suggested a practical approach for the diagnosis, classification and initial clinical treatment of mastocytosis. PMID:24141298

  8. Mast Cell Stabilizer Ketotifen Inhibits Gouty Inflammation in Rats.

    PubMed

    Hsu, Dur-Zong; Chu, Pei-Yi; Chen, Si-Jin; Liu, Ming-Yie

    2016-01-01

    Gout, an extremely painful arthritis with relapsing inflammatory attacks, is a common inflammatory joint disease in adults. We examined the therapeutic effect of ketotifen, a mast cell stabilizer, on monosodium urate (MSU) crystal-induced acute inflammation. Eight-week-old male Wistar rats were injected with MSU crystals (5 mg per rat) into air pouch. Ketotifen (0, 0.1, 03, and 1 mg/kg) was given 1 hour before MSU crystal injection. Lavage histamine, leukocyte counts, mast cell counts, nitric oxide, and proinflammatory mediator levels were assessed 12 hours after MSU injection. Ketotifen significantly inhibited MSU-induced mast cell activation and histamine concentration in air pouch lavage. Ketotifen dose-dependently inhibited MSU-initiated leukocyte infiltration into the air pouch. Furthermore, ketotifen significantly decreased proinflammatory mediators, including nitric oxide, interleukin-1β, and interleukin-6, production in MSU-treated rats. Ketotifen may attenuate MSU-induced acute inflammation by inhibiting mast cell activation and leukocyte infiltration in rats. Furthermore, ketotifen has the potential to be a new approach in managing patients with gouty inflammation in the future. PMID:23884077

  9. Sphingosine-1-phosphate and other lipid mediators generated by mast cells as critical players in allergy and mast cell function.

    PubMed

    Kulinski, Joseph M; Muñoz-Cano, Rosa; Olivera, Ana

    2016-05-01

    Sphingosine-1-phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. PMID:25941085

  10. Methods for the study of mast cells in cancer.

    PubMed

    Blatner, Nichole R; Tsai, FuNien; Khazaie, Khashayarsha

    2015-01-01

    Tumor growth requires interactions of tumor cells with a receptive and inductive microenvironment. Two major populations of tumor-infiltrating cells are considered to be essential for producing such a microenvironment: (1) proinflammatory cells that nurture the tumor with growth factors and facilitate invasion and metastasis by secreting proteases and (2) immune suppressive leukocytes including T-regulatory cells (Treg) that hinder tumor-specific CD8 T-cell responses, which otherwise could potentially reject the tumor. Among the proinflammatory cells, accumulation of mast cells (MCs) in human tumors is frequently recorded and was recently linked with poor prognosis. Causative links between mast cell infiltration and tumor progression can be deduced from animal studies. There is an interesting link between mast cells and Treg. The adoptive transfer of Treg from healthy syngeneic mice to mice susceptible to colon cancer suppresses focal mastocytosis and hinders tumor progression. Furthermore, T-cell-deficient mice susceptible to colon cancer show enhanced focal mastocytosis and tumor invasion. Here, we describe methods to assess MCs in mouse models of cancer and to investigate how MCs affect tumor epithelium. Additionally, we will detail methods used to investigate how T cells influence MCs and how MCs influence T cells. PMID:25388267

  11. Comparative functional characterization of mouse bone marrow-derived mast cells and peritoneal mast cells in response to non-immunological stimuli.

    PubMed

    Singh, R; Kumar, P; Gupta, P P

    2001-04-01

    The cultured mouse mast cells that are dependent on spleen-derived factor for their proliferation and maintenance and have been shown to be similar to mucosal mast cells in terms of their T-cell dependence and histochemical staining characteristics. Mast cell heterogeneity has been confirmed by functional characterization of mouse bone marrow-derived mast cells (MBMMC) and mouse peritoneal mast cells (MPMCs). MPMCs released around 30% of histamine when stimulated with compound 48/80 whereas MBMMC were almost unresponsive to the same stimulus. Calcium Ionophore A23187 on the other hand, released histamine in dose-dependent manner from MBMMC. The study was undertaken to investigate the effect of antiallergic drug, disodium cromoglycate (DSCG), a synthetic cromone and quercetin, a plant-derived flavonoid on Ca ionophore A23187 induced histamine release from MBMMC. MBMMCs were almost unresponsive to DSCG whereas Ca Ionophore induced histamine release was blocked by Quercetin. The results indicate that response of mast cells at one anatomic site to a given stimulus does not necessarily predict the response of mast cells at a different anatomic location to the same stimulus. It shows functional heterogeneity within a single species. So, it cannot be assumed that antiallergic compounds stabilizing mast cells in one tissue site or organ will be equally efficacious against mast cells in other sites. PMID:11491575

  12. Interleukin-33 and Mast Cells Bridge Innate and Adaptive Immunity: From the Allergologist’s Perspective

    PubMed Central

    Jang, Tae Young; Kim, Young Hyo

    2015-01-01

    Interleukin (IL) 33, a member of the IL-1 superfamily, is an “alarmin” protein and is secreted in its active form from damaged cells undergoing necrotic cell death. Mast cells are one of the main effector cell types in allergic disorders. They secrete a variety of mediators, including T helper 2 cytokines. As mast cells have high-affinity IgE receptors (FcεRI) on their surface, they can capture circulating IgE. IgE-bound mast cells degranulate large amounts of histamine, heparin, and proteases when they encounter antigens. As IL-33 is an important mediator of innate immunity and mast cells play an important role in adaptive immune responses, interactions between the two could link innate and adaptive immunity. IL-33 promotes the adhesion of mast cells to laminin, fibronectin, and vitronectin. IL-33 increases the expression of adhesion molecules, such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, in endothelial cells, thus enhancing mast cell adhesion to blood vessel walls. IL-33 stimulates mast cell proliferation by activating the ST2/Myd88 pathway; increases mast cell survival by the activation of survival proteins such as Bcl-XL; and promotes the growth, development, and maturation of mast cell progenitors. IL-33 is also involved in the activation of mature mast cells and production of different proinflammatory cytokines. The interaction of IL-33 and mast cells could have important clinical implications in the field of clinical urology. Epithelial dysfunction and mast cells could play an important role in the pathogenesis of interstitial cystitis. Urinary levels of IL-33 significantly increase in patients with interstitial cystitis. In addition, the number of mast cells significantly increase in the urinary bladders of patients with interstitial cystitis. Therefore, inhibition of mast cell activation and degranulation in response to increase in IL-33 is a potential therapeutic target in the treatment of interstitial cystitis

  13. Signal transduction pathways in mast cell granule-mediated endothelial cell activation.

    PubMed Central

    Chi, Luqi; Stehno-Bittel, Lisa; Smirnova, Irina; Stechschulte, Daniel J; Dileepan, Kottarappat N

    2003-01-01

    BACKGROUND: We have previously shown that incubation of human endothelial cells with mast cell granules results in potentiation of lipopolysaccharide-induced production of interleukin-6 and interleukin-8. AIMS: The objective of the present study was to identify candidate molecules and signal transduction pathways involved in the synergy between mast cell granules and lipopolysaccharide on endothelial cell activation. METHODS: Human umbilical vein endothelial cells were incubated with rat mast cell granules in the presence and absence of lipopolysaccharide, and IL-6 production was quantified. The status of c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2 activation, nuclear factor-kappaB translocation and intracellular calcium levels were determined to identify the mechanism of synergy between mast cell granules and lipopolysaccaride. RESULTS: Mast cell granules induced low levels of interleukin-6 production by endothelial cells, and this effect was markedly enhanced by lipopolysaccharide. The results revealed that both serine proteases and histamine present in mast cell granules were involved in this activation process. Mast cell granules increased intracellular calcium, and activated c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2. The combination of lipopolysaccharide and mast cell granules prolonged c-Jun amino-terminal kinase activity beyond the duration of induction by either stimulant alone and was entirely due to active proteases. However, both proteases and histamine contributed to calcium mobilization and extracellular signal-regulated kinase 1/2 activation. The nuclear translocation of nuclear factor-kappaB proteins was of greater magnitude in endothelial cells treated with the combination of mast cell granules and lipopolysaccharide. CONCLUSIONS:Mast cell granule serine proteases and histamine can amplify lipopolysaccharide-induced endothelial cell activation, which involves calcium mobilization, mitogen

  14. Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice

    PubMed Central

    Chatterjea, Devavani; Wetzel, Abigail; Mack, Madison; Engblom, Camilla; Allen, Juliann; Mora-Solano, Carolina; Paredes, Luisa; Balsells, Evelyn; Martinov, Tijana

    2012-01-01

    Mast cells mediate allergies, hypersensitivities, host defense, and venom neutralization. An area of recent interest is the contribution of mast cells to inflammatory pain. Here we found that specific, local activation of mast cells produced plantar hyperalgesia in mice. Basic secretagogue compound 48/80 induced plantar mast cell degranulation accompanied by thermal hyperalgesia, tissue edema, and neutrophil influx in the hindpaws of ND4 Swiss mice. Blocking mast cell degranulation, neutrophil extravasation, and histamine signaling abrogated these responses. Compound 48/80 also produced edema, pain, and neutrophil influx in WT C57BL/6 but not in genetically mast cell-deficient C57BL/6-KitW-sh/W-sh mice. These responses were restored following plantar reconstitution with bone marrow-derived cultured mast cells. PMID:22828511

  15. Further characterization of protein kinase C in mouse mast cells

    SciTech Connect

    White, J.R.; Ishizaka, T.

    1986-03-01

    Bridging of cell-bound IgE antibody molecules on colony stimulating factor dependent mouse mast cell line (PT-18) cells by multivalent antigen induces the mobilization and uptake of Ca/sup 2 +/ monitored by Quin-2 and the production of diacylglycerol. Exposure of the sensitized cells to antigen also induces a substantial increase in protein kinase C (PKC) activity in the plasma membrane (340 units to 1375 units: 1 unit = 1 pmol of /sup 32/P incorporated into Histone H-1/min/10/sup 7/ cells), within 30 seconds. There is also an increase in /sup 3/H phorbol-12, 13-dibutyrate (/sup 3/H-PDB) binding which parallels the increase in PKC activity both in kinetics and antigen dose dependency. Determination of K/sub m/ and V/sub max/ for PKC revealed no difference between the cytosolic and membranous forms of PKC. Partial purification of PKC from the membrane of sensitized mast cells which had been labeled with /sup 32/P and stimulated with DNP-HSA revealed a protein of 80-84,000 molecular weight, which migrated on polyacrylamide gel electrophoresis just above an authentic standard of PKC purified from rat brain. Treatment of the PKC from mouse mast cell membrane with alkaline phosphatase resulted in a reduction of phosphorylating activity and bindability of /sup 3/H-PDB. In conclusion, the authors speculate that activation of mouse mast cells by cross-linking IgE results in the phosphorylation of a silent-pool of PKC converting it from an inactive state to an activated form.

  16. Inhibitory effects of curcumin on passive cutaneous anaphylactoid response and compound 48/80-induced mast cell activation

    PubMed Central

    Choi, Yun-Ho; Yan, Guang-Hai; Chai, Ok Hee

    2010-01-01

    Mast cells participate in allergies and inflammation by secreting a variety of pro-inflammatory mediators. Curcumin, the active component of turmeric, is a polyphenolic phytochemical with anti-tumor, anti-inflammatory, anti-oxidative, and anti-allergic properties. The effects of curcumin on compound 48/80-induced mast cell activation and passive cutaneous anaphylactoid reactions are unknown. In this report, we investigated the influences of curcumin on the passive cutaneous anaphylactoid response in vivo and compound 48/80-induced mast cell activation in vitro. The mechanism of action was examined by calcium uptake measurements and cAMP assays in mast cells. Curcumin significantly attenuated the mast cell-mediated passive cutaneous anaphylactoid reaction in an animal model. In agreement with this in vivo activity, curcumin suppressed compound 48/80-induced rat peritoneal mast cell (RPMC) degranulation and histamine release from RPMCs. Moreover, compound 48/80-elicited calcium uptake into RPMCs was reduced in a dose-dependent manner by curcumin. Furthermore, curcumin increased the level of intracellular cAMP and significantly inhibited the compound 48/80-induced reduction of cAMP in RPMCs. These results corroborate the finding that curcumin may have anti-allergic activity. PMID:21190003

  17. Identification of a lysophosphatidylserine receptor on mast cells.

    PubMed

    Sugo, Tsukasa; Tachimoto, Hiroshi; Chikatsu, Tomoko; Murakami, Yuko; Kikukawa, Yuhsuke; Sato, Shuji; Kikuchi, Kuniko; Nagi, Toshimi; Harada, Mioko; Ogi, Kazuhiro; Ebisawa, Motohiro; Mori, Masaaki

    2006-03-24

    Lysophosphatidyl-L-serine (lysoPS) is thought to be an immunological regulator because it dramatically augments the degranulation of rat peritoneal mast cells (RPMCs). This stimulatory effect may be mediated by a lysoPS receptor, but its molecule has not been identified yet. During a ligand fishing study for the orphan G-protein-coupled receptor 34 (GPR34), we found that lysoPS caused a dose-dependent inhibition of forskolin-stimulated cAMP accumulation in human GPR34-expressing Chinese hamster ovary (CHO/hGPR34) cells. The CHO/hGPR34 cells were unresponsive to other structurally related phospholipids examined. Quantitative real-time-PCR demonstrated that mRNAs of GPR34 are particularly abundant in mast cells. The effective lysoPS concentration for RPMC degranulation was similar to that required for GPR34 activation, and the structural requirement of lysoPS for RPMC degranulation was in good agreement with that observed in CHO/hGPR34 cells. These results suggest that GPR34 is the functional mast cell lysoPS receptor. PMID:16460680

  18. IgE and Mast Cells: The Endogenous Adjuvant.

    PubMed

    Oettgen, Hans C; Burton, Oliver T

    2015-01-01

    Mast cells and immunoglobulin E (IgE) are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive cells of the immune system. In this purview, they act as endogenous adjuvants to ignite evolving immune responses, promote the transition of allergic disease into chronic illness, and disrupt the development of active mechanisms of tolerance to ingested foods. Suppression of IgE-mediated mast cell activation can be exerted by molecules targeting IgE, FcɛRI, or signaling kinases including Syk, or by IgG antibodies acting via inhibitory Fcγ receptors. Recent reports indicate that such interventions have promise in the development of strategies to treat allergic disease. PMID:26073985

  19. Sphingosine-1-phosphate synthesis and functions in mast cells

    PubMed Central

    Price, Megan M; Oskeritzian, Carole A; Milstien, Sheldon; Spiegel, Sarah

    2009-01-01

    Sphingolipids are not only major lipid components of all eukaryotic cell membranes, but they also comprise an important family of bioactive signaling molecules that regulate a diverse array of biological responses. The sphingolipid metabolite sphingosine-1-phosphate (S1P), is a key regulator of immune responses. Cellular levels of S1P are determined by the balance between its synthesis, involving two sphingosine kinases (SphK1 and SphK2), and its degradation, involving S1P lyase and S1P phosphatases. S1P mainly signals through its cell-surface receptors and may also have intracellular functions. S1P has important functions in mast cells – the major effectors of allergic responses. Antigen triggering of IgE receptors on mast cells activates both SphKs resulting in the production of S1P that is released and regulates and amplifies mast cell functions, including degranulation as well as cytokine and chemokine release. PMID:19802381

  20. Different radiosensitivities of mast-cell precursors in the bone marrow and skin of mice

    SciTech Connect

    Kitamura, Y.; Yokoyama, M.; Sonoda, T.; Mori, K.J.

    1983-01-01

    Although tissue mast cells are derived from the bone marrow, some descendants of bone marrow-derived precursors retain the ability to proliferate and differentiate into mast cells even after localization in the skin. The purpose of the present study was to determine the D/sub 0/ values for mast-cell precursors in the bone marrow and those localized in the skin. Bone marrow cells were removed from (WB X C57BL/6)F/sub 1/+/+ mice after various doses of irradiation and injected into the skin of the congenic W/W/sup v/ mice which were genetically without mast cells. Radiosensitivity of mast-cell precursors in the bone marrow was evaluated by determining the proportion of the injection sites at which mast cells did not appear. For the assay of the radiosensitivity of mast-cell precursors localized in the skin, pieces of skin were removed from beige C57BL/6 (bg/sup J//bg/sup J/, Chediak-Higashi syndrome) mice after various doses of irradiation and grafted onto the backs of the normal C57BL/6 mice. Radiosensitivity of mast-cell precursors in the skin was evaluated by determining the decrease of beige-type mast cells which possessed giant granules. Mast-cell precursors in the bone marrow were much more radiosenitive than those localized in the skin. D/sup 0/ value was about 100 rad for the former and about 800 rad for the latter.

  1. Different radiosensitivities of mast-cell precursors in the bone marrow and skin of mice

    SciTech Connect

    Kitamura, Y.; Yokoyama, M.; Sonoda, T.; Mori, K.J.

    1983-01-01

    Although tissue mast cells are derived from the bone marrow, some descendants of bone marrow-derived precursors retain the ability to proliferate and differentiate into mast cells even after localization in the skin. The purpose of the present study was to determine the D0 values for mast-cell precursors in the bone marrow and those localized in the skin. Bone marrow cells were removed from (WB X C57BL/6)F1-+/+ mice after various doses of irradiation and injected into the skin of the congenic W/Wv mice which were genetically without mast cells. Radiosensitivity of mast-cell precursors in the bone marrow was evaluated by determining the proportion of the injection sites at which mast cells did not appear. For the assay of the radiosensitivity of mast-cell precursors localized in the skin, pieces of skin were removed from beige C57BL/6 (bgJ/bgJ. Chediak-Higashi syndrome) mice after various doses of irradiation and grafted onto the back of the normal C57BL/6 mice. Radiosensitivity of mast-cell precursors in the skin was evaluated by determining the decrease of beige-type mast cells which possessed giant granules. Mast-cell precursors in the bone marrow were much more radiosensitive than those localized in the skin. D0 value was about 100 rad for the former and about 800 rad for the latter.

  2. Mast Cells as Regulators of T Cell Responses.

    PubMed

    Bulfone-Paus, Silvia; Bahri, Rajia

    2015-01-01

    Mast cells (MCs) are recognized to participate in the regulation of innate and adaptive immune responses. Owing to their strategic location at the host-environment interface, they control tissue homeostasis and are key cells for starting early host defense against intruders. Upon degranulation induced, e.g., by immunoglobulin E (IgE) and allergen-mediated engagement of the high-affinity IgE receptor, complement or certain neuropeptide receptors, MCs release a wide variety of preformed and newly synthesized products including proteases, lipid mediators, and many cytokines, chemokines, and growth factors. Interestingly, increasing evidence suggests a regulatory role for MCs in inflammatory diseases via the regulation of T cell activities. Furthermore, rather than only serving as effector cells, MCs are now recognized to induce T cell activation, recruitment, proliferation, and cytokine secretion in an antigen-dependent manner and to impact on regulatory T cells. This review synthesizes recent developments in MC-T cell interactions, discusses their biological and clinical relevance, and explores recent controversies in this field of MC research. PMID:26300882

  3. Mast Cells as Regulators of T Cell Responses

    PubMed Central

    Bulfone-Paus, Silvia; Bahri, Rajia

    2015-01-01

    Mast cells (MCs) are recognized to participate in the regulation of innate and adaptive immune responses. Owing to their strategic location at the host–environment interface, they control tissue homeostasis and are key cells for starting early host defense against intruders. Upon degranulation induced, e.g., by immunoglobulin E (IgE) and allergen-mediated engagement of the high-affinity IgE receptor, complement or certain neuropeptide receptors, MCs release a wide variety of preformed and newly synthesized products including proteases, lipid mediators, and many cytokines, chemokines, and growth factors. Interestingly, increasing evidence suggests a regulatory role for MCs in inflammatory diseases via the regulation of T cell activities. Furthermore, rather than only serving as effector cells, MCs are now recognized to induce T cell activation, recruitment, proliferation, and cytokine secretion in an antigen-dependent manner and to impact on regulatory T cells. This review synthesizes recent developments in MC–T cell interactions, discusses their biological and clinical relevance, and explores recent controversies in this field of MC research. PMID:26300882

  4. Mast cells, basophils and B cell connection network.

    PubMed

    Merluzzi, Sonia; Betto, Elena; Ceccaroni, Alice Amaranta; Magris, Raffaella; Giunta, Marina; Mion, Francesca

    2015-01-01

    It has been proven that both resting and activated mast cells (MCs) and basophils are able to induce a significant increase in proliferation and survival of naïve and activated B cells, and their differentiation into antibody-producing cells. The immunological context in which this regulation occurs is of particular interest and the idea that these innate cells induce antibody class switching and production is increasingly gaining ground. This direct role of MCs and basophils in acquired immunity requires cell to cell contact as well as soluble factors and exosomes. Here, we review our current understanding of the interaction between B cells and MCs or basophils as well as the evidence supporting B lymphocyte-MC/basophil crosstalk in pathological settings. Furthermore, we underline the obscure aspects of this interaction that could serve as important starting points for future research in the field of MC and basophil biology in the peculiar context of the connection between innate and adaptive immunity. PMID:24671125

  5. Elemental levels in mast cell granules differ in sections from normal and diabetic rats: an X-ray microanalysis study

    SciTech Connect

    Kendall, M.D.

    1988-03-01

    Mast cells around the thymus of rats stain red with alcian blue and safranin indicating that the mast cells are probably of the peritoneal (connective tissue) type. After the onset of streptozotocin induced diabetes some cells contain both red and blue granules and blue staining cells may appear. X-ray microanalysis of frozen freeze-dried sections from diabetic male CSE Wistar rats showed electron dense granules to have similar amounts of S to normal rat mast cell granules but reduced levels of Na, Mg, P, Cl and K. Two cells also had electron lucent granules with very high levels of Na, Cl, K and Ca and reduced concentrations of S. The differences in elemental composition suggest that the mast cells from diabetic rats are not immature, but are related to the condition of induced diabetes, and that granules of very different composition can occur within a single cell. X-ray microanalysis has given an insight into mast cell granule elemental content which was not possible by conventional biochemical methods.

  6. Two-step differentiation of mast cells from induced pluripotent stem cells.

    PubMed

    Yamaguchi, Tomoko; Tashiro, Katsuhisa; Tanaka, Satoshi; Katayama, Sumie; Ishida, Waka; Fukuda, Ken; Fukushima, Atsuki; Araki, Ryoko; Abe, Masumi; Mizuguchi, Hiroyuki; Kawabata, Kenji

    2013-03-01

    Mast cells play important roles in the pathogenesis of allergic diseases. They are generally classified into 2 phenotypically distinct populations: connective tissue-type mast cells (CTMCs) and mucosal-type mast cells (MMCs). The number of mast cells that can be obtained from tissues is limited, making it difficult to study the function of mast cells. Here, we report the generation and characterization of CTMC-like mast cells derived from mouse induced pluripotent stem (iPS) cells. iPS cell-derived mast cells (iPSMCs) were generated by the OP9 coculture method or embryoid body formation method. The number of Safranin O-positive cells, expression levels of CD81 protein and histidine decarboxylase mRNA, and protease activities were elevated in the iPSMCs differentiated by both methods as compared with those in bone marrow-derived mast cells (BMMCs). Electron microscopic analysis revealed that iPSMCs contained more granules than BMMCs. Degranulation was induced in iPSMCs after stimulation with cationic secretagogues or vancomycin. In addition, iPSMCs had the ability to respond to stimulation with the IgE/antigen complex in vitro and in vivo. Moreover, when iPSMCs generated on OP9 cells were cocultured with Swiss 3T3 fibroblasts, protease activities as maturation index were more elevated, demonstrating that mature mast cells were differentiated from iPS cells. iPSMCs can be used as an in vitro model of CTMCs to investigate their functions. PMID:23045993

  7. Dual effects of protoporphyrin and long wave ultraviolet light on histamine release from rat peritoneal and cutaneous mast cells

    SciTech Connect

    Yen, A.; Gigli, I.; Barrett, K.E. )

    1990-06-01

    In this study we investigated the effects of long wave ultraviolet light (UVA) and various doses of protoporphyrin (PP) on the release of histamine from rat peritoneal and cutaneous mast cells. We also correlated these results with morphologic characteristics and viability of the cells. PP at a dose of 30 ng/ml plus UVA-induced negligible histamine release from rat peritoneal mast cells (RPMC), but was able to suppress the ability of the cells to release histamine in response to subsequent exposure to the calcium ionophore A23187, compound 48/80, or the combination of Ag and IgE. This functional change was associated with an increase in cell size, and cell lysis that gradually occurred during 24 h in culture. PP at a dose of 3 ng/ml plus UVA also significantly inhibited secretogogue-induced histamine release from rat peritoneal mast cells, but this dose was not associated with significant changes in morphology or viability. These various effects of PP plus UVA were also observed with mast cell preparations obtained by the enzymatic dispersion of rat skin. The suppression of secretogogue-induced histamine release in rat peritoneal mast cells treated with PP (3 ng/ml) and UVA could not be reversed by culturing the cells in the dark for 24 h in the absence of PP. Unlike the direct cytotoxic histamine releasing action of high doses of PP plus UVA, the suppressive effect of low PP doses could not be inhibited by catalase, but could be reduced by the absence of calcium. Our results indicate that PP plus UVA has dual effects on mast cells, apparently involving distinct mechanisms. This implies the possibility that PP and UVA at appropriate doses could be used in photochemotherapy of mast cell-mediated skin diseases.

  8. Relationship between Mast Cells and the Colitis with Relapse Induced by Trinitrobenzesulphonic Acid in Wistar Rats

    PubMed Central

    Luchini, Ana Carolina; Costa de Oliveira, Déborah Mara; Pellizzon, Cláudia Helena; Di Stasi, Luiz Claudio; Gomes, José Carlos

    2009-01-01

    The present study aimed to clarify the role of mast cells in colitis with relapse induced in Wistar rats by trinitrobenzenosulphonic acid. Colitis induction increased the histamine concentration in the colon, which peaked on day 26. The number of mast cells, probably immature, was ten times higher on day 8. Different from animals infected with intestinal parasites, after colitis remission, mast cells do not migrate to the spleen, showing that mast cell proliferation presents different characteristics depending on the inflammation stimuli. Treatment with sulfasalazine, doxantrazole, quercetin, or nedocromil did not increase the histamine concentration or the mast cell number in the colon on day 26, thereby showing absence of degranulation of these cells. In conclusion, although mast cell proliferation is associated with colitis, these cells and their mediators appear to play no clear role in the colitis with relapses. PMID:19436763

  9. The role of mast cells in functional GI disorders.

    PubMed

    Wouters, Mira M; Vicario, Maria; Santos, Javier

    2016-01-01

    Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16-26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. Their etiopathogenic mechanisms remain unclear, however, recent observations reveal low-grade mucosal inflammation and immune activation, in association with impaired epithelial barrier function and aberrant neuronal sensitivity. These findings come to challenge the traditional view of FGIDs as pure functional disorders, and relate the origin to a tangible organic substrate. The mucosal inflammatory infiltrate is dominated by mast cells, eosinophils and intraepithelial lymphocytes in the intestine of FGIDs. It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease. This review will discuss the role of mucosal mast cells in the gastrointestinal tract with a specific focus on recent advances in disease mechanisms and clinical management in irritable bowel syndrome and functional dyspepsia. PMID:26194403

  10. The dark side of mast cell-targeted therapy in prostate cancer.

    PubMed

    Pittoni, Paola; Colombo, Mario Paolo

    2012-02-15

    Tumor development requires accomplices among white blood cells. Other than macrophages, mast cells have been observed to support the outgrowth of certain neoplasias because of their proangiogenic properties. In some tumor settings, however, mast cells may have a protective role, exerted by their proinflammatory mediators. In prostate cancer, no conclusive data on mast cell function were available. Here, we discuss recent work on the role of mast cells in mouse and human prostate cancer, showing that mast cells can behave alternatively as dangerous promoters, innocent bystanders, or essential guardians of tumors, according to the stage and origin of transformed cells. In particular, mast cells are essential for the outgrowth of early-stage tumors due to their matrix metalloproteinase-9 production, become dispensable in advanced-stage, post-epithelial-to-mesenchymal transition, and are protective against neuroendocrine prostate tumor variants. The common expression of c-Kit by mast cells and neuroendocrine clones suggests a possible competition for the ligand Stem cell factor and offers the chance of curing early-stage disease while preventing neuroendocrine tumors using c-Kit-targeted therapy. This review discusses the implications of these findings on the advocated mast cell-targeted cancer therapy and considers future directions in the study of mast cells and their interactions with other c-Kit-expressing cells. PMID:22307838

  11. Induction of Mast Cell Accumulation by Tryptase via a Protease Activated Receptor-2 and ICAM-1 Dependent Mechanism

    PubMed Central

    Liu, Xin; Wang, Junling; Zhang, Huiyun; Zhan, Mengmeng; Chen, Hanqiu; Fang, Zeman; Xu, Chiyan; Chen, Huifang; He, Shaoheng

    2016-01-01

    Mast cells are primary effector cells of allergy, and recruitment of mast cells in involved tissue is one of the key events in allergic inflammation. Tryptase is the most abundant secretory product of mast cells, but little is known of its influence on mast cell accumulation. Using mouse peritoneal model, cell migration assay, and flow cytometry analysis, we investigated role of tryptase in recruiting mast cells. The results showed that tryptase induced up to 6.7-fold increase in mast cell numbers in mouse peritoneum following injection. Inhibitors of tryptase, an antagonist of PAR-2 FSLLRY-NH2, and pretreatment of mice with anti-ICAM-1, anti-CD11a, and anti-CD18 antibodies dramatically diminished tryptase induced mast cell accumulation. On the other hand, PAR-2 agonist peptides SLIGRL-NH2 and tc-LIGRLO-NH2 provoked mast cell accumulation following injection. These implicate that tryptase induced mast cell accumulation is dependent on its enzymatic activity, activation of PAR-2, and interaction between ICAM-1 and LFA-1. Moreover, induction of trans-endothelium migration of mast cells in vitro indicates that tryptase acts as a chemoattractant. In conclusion, provocation of mast cell accumulation by mast cell tryptase suggests a novel self-amplification mechanism of mast cell accumulation. Mast cell stabilizers as well as PAR-2 antagonist agents may be useful for treatment of allergic reactions. PMID:27378825

  12. Human mast cells decrease SLPI levels in type II – like alveolar cell model, in vitro

    PubMed Central

    Hollander, Camilla; Nyström, Max; Janciauskiene, Sabina; Westin, Ulla

    2003-01-01

    Background Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. Result We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p < 0.01) in a SLPI-producing, type II-like alveolar cell line, (A549) when co-cultured with HMC-1 cells, but not in an HMC-1-conditioned medium, for 96 hours. By contrast, increased SLPI mRNA expression (by 1.58-fold, p < 0.05) was found under the same experimental conditions. Immunohistochemical analysis revealed mast cell transmigration in co-culture with SLPI-producing A549 cells for 72 and 96 hours. Conclusion These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response. PMID:12952550

  13. Mast Cells Condition Dendritic Cells to Mediate Allograft Tolerance

    PubMed Central

    de Vries, Victor C.; Pino-Lagos, Karina; Nowak, Elizabeth C.; Bennett, Kathy A.; Oliva, Carla; Noelle, Randolph J.

    2013-01-01

    SUMMARY Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior (“conditioning”) to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs. PMID:22035846

  14. Dengue Virus Infection of Mast Cells Triggers Endothelial Cell Activation ▿

    PubMed Central

    Brown, Michael G.; Hermann, Laura L.; Issekutz, Andrew C.; Marshall, Jean S.; Rowter, Derek; Al-Afif, Ayham; Anderson, Robert

    2011-01-01

    Vascular perturbation is a hallmark of severe forms of dengue disease. We show here that antibody-enhanced dengue virus infection of primary human cord blood-derived mast cells (CBMCs) and the human mast cell-like line HMC-1 results in the release of factor(s) which activate human endothelial cells, as evidenced by increased expression of the adhesion molecules ICAM-1 and VCAM-1. Endothelial cell activation was prevented by pretreatment of mast cell-derived supernatants with a tumor necrosis factor (TNF)-specific blocking antibody, thus identifying TNF as the endothelial cell-activating factor. Our findings suggest that mast cells may represent an important source of TNF, promoting vascular endothelial perturbation following antibody-enhanced dengue virus infection. PMID:21068256

  15. Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6.

    PubMed

    Vangansewinkel, Tim; Geurts, Nathalie; Quanten, Kirsten; Nelissen, Sofie; Lemmens, Stefanie; Geboes, Lies; Dooley, Dearbhaile; Vidal, Pia M; Pejler, Gunnar; Hendrix, Sven

    2016-05-01

    An important barrier for axon regeneration and recovery after traumatic spinal cord injury (SCI) is attributed to the scar that is formed at the lesion site. Here, we investigated the effect of mouse mast cell protease (mMCP) 6, a mast cell (MC)-specific tryptase, on scarring and functional recovery after a spinal cord hemisection injury. Functional recovery was significantly impaired in both MC-deficient and mMCP6-knockout (mMCP6(-/-)) mice after SCI compared with wild-type control mice. This decrease in locomotor performance was associated with an increased lesion size and excessive scarring at the injury site. Axon growth-inhibitory chondroitin sulfate proteoglycans and the extracellular matrix components fibronectin, laminin, and collagen IV were significantly up-regulated in MC-deficient and mMCP6(-/-) mice, with an increase in scar volume between 23 and 32%. A degradation assay revealed that mMCP6 directly cleaves fibronectin and collagen IV in vitro In addition, gene expression levels of the scar components fibronectin, aggrecan, and collagen IV were increased up to 6.8-fold in mMCP6(-/-) mice in the subacute phase after injury. These data indicate that endogenous mMCP6 has scar-suppressing properties after SCI via indirect cleavage of axon growth-inhibitory scar components and alteration of the gene expression profile of these factors.-Vangansewinkel, T., Geurts, N., Quanten, K., Nelissen, S., Lemmens, S., Geboes, L., Dooley, D., Vidal, P. M., Pejler, G., Hendrix, S. Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6. PMID:26917739

  16. Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.

    PubMed

    Cruz, E A; Reuter, S; Martin, H; Dehzad, N; Muzitano, M F; Costa, S S; Rossi-Bergmann, B; Buhl, R; Stassen, M; Taube, C

    2012-01-15

    Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant. PMID:21802918

  17. Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4

    PubMed Central

    Torres-Atencio, Ivonne; Ainsua-Enrich, Erola; de Mora, Fernando; Picado, César; Martín, Margarita

    2014-01-01

    Background Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1–4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition. PMID:25329458

  18. Damnacanthal inhibits IgE receptor-mediated activation of mast cells.

    PubMed

    Garcia-Vilas, Javier A; Medina, Miguel A; Melo, Fabio R; Pejler, Gunnar; Garcia-Faroldi, Gianni

    2015-05-01

    Damnacanthal, an anthraquinone obtained from the noni fruit (Morinda citrifolia L.), has been described to possess anti-cancer and anti-inflammatory properties. Since mast cells are key players in various inflammatory conditions as well as in cancer, we considered the possibility that the biological actions of damnacanthal, at least partly, could be due to effects on mast cells. Many of the biological activities of mast cells are mediated by IgE receptor cross-linking, which results in degranulation with release of preformed granule mediators, as well as de novo synthesis and release of additional compounds. Here we show that damnacanthal has profound inhibitory activity on mast cell activation through this pathway. The release of the granule compounds beta-hexosaminidase and tryptase release was completely abrogated by damnacanthal at doses that were non-toxic to mast cells. In addition, damnacanthal inhibited activation-dependent pro-inflammatory gene induction, as well as cytokine/chemokine release in response to mast cell stimulation. The mechanism underlying damnacanthal inhibition was linked to impaired phosphorylation of Syk and Akt. Furthermore, damnacanthal inhibited mast cell activation in response to calcium ionophore A23187. Altogether, the data presented here demonstrate that damnacanthal inhibits mast cell activation induced by different stimuli and open a new window for the use of this compound as a mast cell stabilizer. PMID:25656801

  19. Tumor microvessel density–associated mast cells in canine nodal lymphoma

    PubMed Central

    Mann, Elizabeth; Whittington, Lisa

    2014-01-01

    Objective: Mast cells are associated in angiogenesis in various human and animal neoplasms. However, association of mast cells with tumor microvessel density in canine lymphoma was not previously documented. The objective of the study is to determine if mast cells are increased in canine nodal lymphomas and to evaluate their correlation with tumor microvessel density and grading of lymphomas. Methods: Nodal lymphomas from 33 dogs were studied and compared with nonneoplastic lymph nodes from 6 dogs as control. Mast cell count was made on Toluidine blue stained sections. Immunohistochemistry using antibody against Factor VIII was employed to visualize and determine microvessel density. Results: The mast cell count in lymphoma (2.95 ± 2.4) was significantly higher (p < 0.05) than that in the control (0.83 ± 0.3) and was positively correlated with tumor microvessel density (r = 0.44, p = 0.009). Significant difference was not observed in mast cell count and tumor microvessel density among different gradings of lymphomas. Conclusions: Mast cells are associated with tumor microvessel density in canine nodal lymphoma with no significant difference among gradings of lymphomas. Mast cells may play an important role in development of canine nodal lymphomas. Further detailed investigation on the role of mast cells as important part of tumor microenvironment in canine nodal lymphomas is recommended. PMID:26770752

  20. ROLE OF MENINGEAL MAST CELLS IN INTRATHECAL MORPHINE EVOKED GRANULOMA FORMATION

    PubMed Central

    Yaksh, Tony L.; Allen, Jeffery W.; Veesart, Samantha L.; Horais, Kjersti A; Malkmus, Shelle A.; Scadeng, Miriam; Steinauer, Joanne J.; Rossi, Steve S

    2013-01-01

    Background Intrathecal morphine forms granulomas that arise from the adjacent arachnoid membrane. We propose that these inflammatory cells exit the meningeal vasculature secondary to meningeal mast cell degranulation. Methods Three sets of experiments were accomplished in dogs. 1) Ex vivo Meningeal mast cell degranulation. Histamine release was measured ex vivo from canine dura incubated with opiates. 2) In vivo cutaneous mast cell degranulation. Flare areas on the dog abdomen were measured after subcutaneous opiates. 3) In vivo granuloma pharmacology. Dogs with lumbar intrathecal catheters received infusion of intrathecal saline or intrathecal morphine. Intrathecal morphine dogs received: i) No other treatment (Control); ii) Twice daily subcutaneous naltrexone; iii) Intrathecal co-infusion of cromolyn; or, iv) Twice daily subcutaneous cromolyn for the 24–28 day study course. Results 1) Morphine but not fentanyl evoked dural histamine release, which was blocked by cromolyn but not naloxone. 2) Wheal/flare was produced by subcutaneous morphine, methadone, hydromorphone, but not fentanyl, and was unaffected by naltrexone but prevented by cromolyn. 3) Granulomas occurred in all dogs receiving intrathecal morphine (15/15); subcutaneous naltrexone had no effect on granulomas (6/6), but was reduced by concurrent intrathecal cromolyn (0/5) or twice daily subcutaneous cromolyn (1 of 5). Conclusions The pharmacology of cutaneous/dural MC degranulation and intrathecal granulomas are comparable, not mediated by opioid receptors, and reduced by agents preventing MC degranulation. If an agent produces cutaneous MC degranulation at concentrations produced by intrathecal delivery, the agent may initiate granulomas. PMID:23426209

  1. The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells.

    PubMed

    Tsai, Shih Han; Kinoshita, Makoto; Kusu, Takashi; Kayama, Hisako; Okumura, Ryu; Ikeda, Kayo; Shimada, Yosuke; Takeda, Akira; Yoshikawa, Soichiro; Obata-Ninomiya, Kazushige; Kurashima, Yosuke; Sato, Shintaro; Umemoto, Eiji; Kiyono, Hiroshi; Karasuyama, Hajime; Takeda, Kiyoshi

    2015-02-17

    Crosslinking of the immunoglobulin receptor FcεRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcεRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations. Enpp3(-/-) mice were highly sensitive to chronic allergic pathologies, which was reduced by ATP blockade. FcεRI crosslinking induced ATP secretion from basophils and mast cells, and ATP activated both cells. ATP clearance was impaired in Enpp3(-/-) cells. Enpp3(-/-)P2rx7(-/-) mice showed decreased responses to FcεRI crosslinking. Thus, ATP released by FcεRI crosslinking stimulates basophils and mast cells for further activation causing allergic inflammation. E-NPP3 decreases ATP concentration and suppresses basophil and mast cell activity. PMID:25692702

  2. Isolation of Mature (Peritoneum-Derived) Mast Cells and Immature (Bone Marrow-Derived) Mast Cell Precursors from Mice

    PubMed Central

    Meurer, Steffen K.; Neß, Melanie; Weiskirchen, Sabine; Kim, Philipp; Tag, Carmen G.; Kauffmann, Marlies; Huber, Michael; Weiskirchen, Ralf

    2016-01-01

    Mast cells (MCs) are a versatile cell type playing key roles in tissue morphogenesis and host defence against bacteria and parasites. Furthermore, they can enhance immunological danger signals and are implicated in inflammatory disorders like fibrosis. This granulated cell type originates from the myeloid lineage and has similarities to basophilic granulocytes, both containing large quantities of histamine and heparin. Immature murine mast cells mature in their destination tissue and adopt either the connective tissue (CTMC) or mucosal (MMC) type. Some effector functions are executed by activation/degranulation of MCs which lead to secretion of a typical set of MC proteases (MCPT) and of the preformed or newly synthesized mediators from its granules into the local microenvironment. Due to the potential accumulation of mutations in key signalling pathway components of corresponding MC cell-lines, primary cultured MCs are an attractive mean to study general features of MC biology and aspects of MC functions relevant to human disease. Here, we describe a simple protocol for the simultaneous isolation of mature CTMC-like murine MCs from the peritoneum (PMCs) and immature MC precursors from the bone marrow (BM). The latter are differentiated in vitro to yield BM-derived MCs (BMMC). These cells display the typical morphological and phenotypic features of MCs, express the typical MC surface markers, and can be propagated and kept in culture for several weeks. The provided protocol allows simple amplification of large quantities of homogenous, non-transformed MCs from the peritoneum and bone marrow-derived mast cells for cell- and tissue-based biomedical research. PMID:27337047

  3. Mast cells and basophils: trojan horses of conventional lin- stem/progenitor cell isolates.

    PubMed

    Heneberg, Petr

    2011-11-01

    Cancer microenvironment is increasingly recognized as an important factor affecting cancer onset and progression. Since Wirchow reported in 1863 that tumors contain inflammatory cells, the field shifted significantly forward, and immune cells residing in tumors appear to be attractive targets of cancer therapies. For some methods, such as stem/progenitor cell isolation from both cancer and healthy tissues, removal of contaminating immune cells is crucial to achieve consistent, reproducible and accurate results. Despite current methods of lineage negative selection accounts for removal of over 99 % of immune cells from stem/progenitor cell isolates, the vast majority of lineage antibody cocktails retain basophils, dendritic cells, and mast cells. Here we discuss the ability of the most commonly used lineage markers to bind to the plasma membrane of mast cells and/or basophils, and suggest alternatives, which may be used for negative selection of these cellular populations. Both, mast cells and basophils, were shown to participate actively in cancer-associated angiogenesis, tissue remodeling and recruitment of other immune cell types, including eosinophils, B cells, memory T cells and Treg cells. In turn, tumor-derived peptides and chemotactic factors are known to recruit and activate mast cells in neoplasias, resulting in altered tumor progression. Repeated findings of CD34+ populations of mast cells and basophils further highlight necessity of their separation from stem/progenitor cell isolates in both, preclinical experiments and clinical praxis. PMID:22103846

  4. Platelet activating factor: regulation by mast cells and aspirin.

    PubMed

    Denburg, J A; Williams, D B; Kinlough-Rathbone, R L; Cazenave, J P; Bienenstock, J

    1984-02-01

    We have investigated some aspects of the regulation of production of rat platelet activating factor (PAF)2 in vitro. Suspensions of unseparated (PLC1), mast cell-depleted (PLC2), or mast cell (MC)-enriched rat peritoneal lavage cells (PLC) were analyzed for PAF content by extraction at alkaline pH. PAF activity extracted from PLC1 varied inversely with viable cell concentration: at 1 X 10(6) cells/ml, 32 +/- 9.3 PAF units, decreasing to 11.2 +/- 9.5 units at 10 X 10(6) cells/ml, and no activity at higher concentrations. Incubation of PLC1 in Tyrode's buffer or acetylsalicylic acid (ASA), but not salicylate, resulted in a time-dependent loss of PAF activity. Mean PAF activity of PLC2 was similar to that in PLC1, while no PAF activity was extractable from MC. Co-incubation with MC extracts inhibited PAF activity of PLC1 extracts in a dose-dependent fashion. Ultracentrifugation of PAF-containing samples led to a loss of all PAF activity in PLC1 extracts, suggesting the association of PAF activity with subcellular components. PAF appears to be derived from a non-MC population of rat PLC, is not extractable from rat PLC in the presence of ASA and is inhibited by MC extracts. These studies suggest that ASA regulates PAF availability unrelated to its effect on cyclooxygenase and that MC membrane products directly inhibit PAF activity from rat PLC. PMID:6711391

  5. Tick Salivary Sialostatin L Represses the Initiation of Immune Responses by Targeting IRF4-Dependent Transcription in Murine Mast Cells.

    PubMed

    Klein, Matthias; Brühl, Till-Julius; Staudt, Valérie; Reuter, Sebastian; Grebe, Nadine; Gerlitzki, Bastian; Hoffmann, Markus; Bohn, Toszka; Ulges, Alexander; Stergiou, Natascha; de Graaf, Jos; Löwer, Martin; Taube, Christian; Becker, Marc; Hain, Tobias; Dietzen, Sarah; Stassen, Michael; Huber, Magdalena; Lohoff, Michael; Campos Chagas, Andrezza; Andersen, John; Kotál, Jan; Langhansová, Helena; Kopecký, Jan; Schild, Hansjörg; Kotsyfakis, Michalis; Schmitt, Edgar; Bopp, Tobias

    2015-07-15

    Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules. PMID:26078269

  6. Tick salivary Sialostatin L represses the initiation of immune responses by targeting IRF4-dependent transcription in murine mast cells

    PubMed Central

    Klein, Matthias; Brühl, Till-Julius; Staudt, Valérie; Reuter, Sebastian; Grebe, Nadine; Gerlitzki, Bastian; Hoffmann, Markus; Bohn, Toszka; Ulges, Alexander; Stergiou, Natascha; de Graaf, Jos; Löwer, Martin; Taube, Christian; Becker, Marc; Hain, Tobias; Dietzen, Sarah; Stassen, Michael; Huber, Magdalena; Lohoff, Michael; Chagas, Andrezza Campos; Andersen, John; Kotál, Jan; Langhansová, Helena; Kopecký, Jan; Schild, Hansjörg; Kotsyfakis, Michalis; Schmitt, Edgar; Bopp, Tobias

    2015-01-01

    Co-evolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. Herein, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells while degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1 receptor-deficient mast cells exhibit strong impairment in IL-9 production demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9 suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction of asthma symptoms demonstrating the immunosuppressive potency of tick-derived molecules. PMID:26078269

  7. Mast Cells Play No Role in the Pathogenesis of Postoperative Ileus Induced by Intestinal Manipulation

    PubMed Central

    Gomez-Pinilla, Pedro J.; Farro, Giovanna; Di Giovangiulio, Martina; Stakenborg, Nathalie; Némethova, Andrea; de Vries, Annick; Liston, Adrian; Feyerabend, Thorsten B.; Rodewald, Hans-Reimwer; Boeckxstaens, Guy E.; Matteoli, Gianluca

    2014-01-01

    Introduction Intestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3Cre/+, devoid of mast cells but with intact Kit signaling. Design The role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. KitW-sh/W-sh and Cpa3Cre/+ mice, and by use of the mast cell stabilizer cromolyn. Results KitW-sh/W-sh mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3Cre/+ mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3Cre/+ mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3+/+). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI. Conclusions Here, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic

  8. The STAT5-GATA2 Pathway Is Critical in Basophil and Mast Cell Differentiation and Maintenance

    PubMed Central

    Li, Yapeng; Qi, Xiaopeng; Liu, Bing; Huang, Hua

    2015-01-01

    Transcription factor GATA2 plays critical roles in hematopoietic stem cell survival and proliferation, GMP differentiation, and basophil and mast cell differentiation. However, precise roles of GATA2 in basophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. We observed Gata2 haploinsufficiency for mast cell differentiation but not for basophil differentiation. We examined the precise role of GATA2 in maintaining the expression of a wide range of genes that are important for performing basophil or mast cell functions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for maintaining Fcer1a mRNA and FcεRIα protein expression on both basophils and mast cells as well as for maintaining Kit mRNA and c-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expression in basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5-GATA2 connection, showing that the STAT5 transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 gene was sufficient to direct basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5-GATA2 pathway is critical for basophil and mast cell differentiation and maintenance. PMID:25801432

  9. Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions

    PubMed Central

    McNeil, Benjamin D.; Pundir, Priyanka; Meeker, Sonya; Han, Liang; Undem, Bradley J.; Kulka, Marianna; Dong, Xinzhong

    2014-01-01

    Mast cells are primary effectors in allergic reactions, and may have significant roles in diseases by secreting histamine and various inflammatory and immunomodulatory substances1,2. While classically they are activated by IgE antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions1,3. Roles for these substances in pathology have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, MrgprB2, the orthologue of the human G-protein coupled receptor (GPCR) MrgprX2. Secretagogue-induced histamine release, inflammation, and airway contraction are abolished in MrgprB2 null mutant mice. Further, we show that most classes of FDA-approved peptidergic drugs associated with allergic-type injection-site reactions also activate MrgprB2 and MrgprX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that MrgprB2 and MrgprX2 are targets of many small molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice, and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MrgprX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects. PMID:25517090

  10. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.

    PubMed

    McNeil, Benjamin D; Pundir, Priyanka; Meeker, Sonya; Han, Liang; Undem, Bradley J; Kulka, Marianna; Dong, Xinzhong

    2015-03-12

    Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects. PMID:25517090

  11. Human Lung Mast Cell Products Regulate Airway Smooth Muscle CXCL10 Levels

    PubMed Central

    Alkhouri, H.; Cha, V.; Tong, K.; Moir, L. M.; Armour, C. L.; Hughes, J. M.

    2014-01-01

    In asthma, the airway smooth muscle (ASM) produces CXCL10 which may attract CXCR3+ mast/T cells to it. Our aim was to investigate the effects of mast cell products on ASM cell CXCL10 production. ASM cells from people with and without asthma were stimulated with IL-1β, TNF-α, and/or IFNγ and treated with histamine (1–100 μM) ± chlorpheniramine (H1R antagonist; 1 μM) or ranitidine (H2R antagonist; 50 μM) or tryptase (1 nM) ± leupeptin (serine protease inhibitor; 50 μM), heat-inactivated tryptase, or vehicle for 4 h or 24 h. Human lung mast cells (MC) were isolated and activated with IgE/anti-IgE and supernatants were collected after 2 h or 24 h. The supernatants were added to ASM cells for 48 h and ASM cell CXCL10 production detected using ELISA (protein) and real-time PCR (mRNA). Histamine reduced IL-1β/TNF-α-induced CXCL10 protein, but not mRNA, levels independent of H1 and H2 receptor activation, whereas tryptase and MC 2 h supernatants reduced all cytokine-induced CXCL10. Tryptase also reduced CXCL10 levels in a cell-free system. Leupeptin inhibited the effects of tryptase and MC 2 h supernatants. MC 24 h supernatants contained TNF-α and amplified IFNγ-induced ASM cell CXCL10 production. This is the first evidence that MC can regulate ASM cell CXCL10 production and its degradation. Thus MC may regulate airway myositis in asthma. PMID:24648846

  12. Modeling Pharmacological Inhibition of Mast Cell Degranulation as a Therapy for Insulinoma12

    PubMed Central

    Soucek, Laura; Buggy, Joseph J; Kortlever, Roderik; Adimoolam, Shanthi; Monclús, Helena Allende; Allende, Maria Teresa Salcedo; Swigart, Lamorna Brown; Evan, Gerard I

    2011-01-01

    Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non-Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases. PMID:22131884

  13. In vitro modeling of rat mucosal mast cell function in Trichinella spiralis infection

    PubMed Central

    Thrasher, Seana M.; Scalfone, Lisa K.; Holowka, David; Appleton, Judith A.

    2012-01-01

    Summary Intestinal infection with the parasitic nematode, Trichinella spiralis, provides a robust context for the study of mucosal mast cell function. In rats, mucosal mast cells are exposed to parasites during the earliest stage of infection, affording an opportunity for mast cells to contribute to an innate response to infection. During secondary infection, degranulation of rat mucosal mast cells coincides with expulsion of challenge larvae from the intestine. The goal of this study was to evaluate rat bone marrow-derived mast cells (BMMC) and the rat basophilic leukemia cell line (RBL-2H3) as models for mucosal mast cells, using parasite glycoproteins and antibody reagents that have been tested extensively in rats in vivo. We found that BMMC displayed a more robust mucosal phenotype. Although T. spiralis glycoproteins bound to mast cell surfaces in the absence of antibodies, they did not stimulate degranulation, nor did they inhibit degranulation triggered by immune complexes. Parasite glycoproteins complexed with specific monoclonal IgGs provoked release of RMCPII and β-hexosaminidase from both cell types in a manner that replicated results observed previously in passively immunized rats. Our results document that RBL-2H3 cells and BMMC model rat mucosal mast cells in the contexts of innate and adaptive responses to T. spiralis. PMID:23094823

  14. Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation.

    PubMed

    Sehra, Sarita; Serezani, Ana P M; Ocaña, Jesus A; Travers, Jeffrey B; Kaplan, Mark H

    2016-07-01

    Atopic dermatitis is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells, and mast cells. The role of mast cells in atopic dermatitis is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of epidermal differentiation complex and other skin genes. Decreased epidermal differentiation complex gene expression in mice that genetically lack mast cells (Kit(W-sh/W-sh) mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells (DCs) compared with similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens. To test this further, we crossed Kit(W-sh/W-sh) mice with signal transducer and activator of transcription 6 (i.e., Stat6) VT transgenic mice that develop spontaneous atopic dermatitis-like disease that is dependent on T helper cell 2 cytokines and is associated with high serum concentrations of IgE. We observed that Stat6VT × Kit(W-sh/W-sh) mice developed more frequent and more severe allergic skin inflammation than Stat6VT transgenic mice that had mast cells. Together, these studies suggest that mast cells regulate epidermal barrier function and have a potential protective role in the development of atopic dermatitis-like disease. PMID:27021404

  15. Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease

    PubMed Central

    Dellon, Evan S.; Chen, Xiaoxin; Miller, C. Ryan; Fritchie, Karen J.; Rubinas, Tara C.; Woosley, John T.; Shaheen, Nicholas J.

    2015-01-01

    Objectives Mast cells may contribute to the pathogenesis of eosinophilic esophagitis (EoE), but their role in diagnosis is unknown. Our aim was to determine whether tryptase staining of esophageal mast cells differentiates EoE from GERD and has utility for diagnosis of EoE. Methods We performed a case-control study comparing patients with EoE, defined by consensus guidelines, to GERD patients with eosinophils on esophageal biopsy. Immunohistochemistry was performed with mast cell tryptase. The density (mast cells/mm2) and intensity (0–4 scale) of mast cell staining was compared between groups after masking the diagnosis. Receiver operating characteristic (ROC) curves were constructed, and the area under the curve (AUC) calculated to assess mast cell staining as both a stand-alone diagnostic test and an adjunctive assay with eosinophil counts. Results Fifty-four EoE (mean age: 24; 69% male; mean 146 eos/hpf) and 55 GERD (mean age 34; 60% male; mean 20 eos/hpf) patients were analyzed. The maximum epithelial tryptase density was higher in EoE than in GERD (162 ± 87 mast cells/mm2 vs 67 ± 54; p<0.001). Mast cells were diffusely distributed throughout the biopsy in more EoE than GERD patients (41% vs 7%; p<0.001). Tryptase density and eosinophil count were only weakly correlated (R2=0.09; p=0.002). The AUC was 0.84 for tryptase staining alone, and 0.96 for the combination of mast cells and eosinophils. Conclusions Patients with EoE have higher levels of tryptase positive mast cells compared to GERD patients, improving the diagnostic value of biopsies beyond eosinophil counts alone. Mast cell tryptase may have utility as a diagnostic assay for EoE. PMID:20978486

  16. Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps

    PubMed Central

    Takabayashi, Tetsuji; Kato, Atsushi; Peters, Anju T.; Suh, Lydia A.; Carter, Roderick; Norton, James; Grammer, Leslie C.; Tan, Bruce K.; Chandra, Rakesh K.; Conley, David B.; Kern, Robert C.; Fujieda, Shigeharu; Schleimer, Robert P.

    2012-01-01

    Background Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the role of mast cells is poorly understood. Objective The objective of this study was to investigate the presence, localization and phenotype of mast cells in patients with chronic rhinosinusitis (CRS). Methods We collected nasal tissue and nasal lavage fluid from patients with CRS and control subjects. We analyzed mRNA for the mast cell proteases tryptase, chymase and carboxypeptidase A3 (CPA3), using real-time PCR, and measured mast cell protease proteins using ELISA, immunohistochemistry, and immunofluorescence. Results Tryptase mRNA was significantly increased in nasal polyps (NPs) from patients with CRSwNP (P < .001) compared with uncinate tissue (UT) from patients with CRS or control subjects. Tryptase protein was also elevated in NPs and in nasal lavage fluids from patients with CRSwNP. Immnohistochemistry showed increased numbers of mast cells in epithelium and glands but not within the lamina propria in NPs. The mast cells detected in epithelium in NPs were characterized by expression of tryptase and CPA3 but not chymase. Mast cells expressing all three proteases were abundant within glandular epithelium of NPs but were not found in normal glandular structures. Conclusion: Herein we demonstrate a unique localization of mast cells within glandular epithelium of NPs, and show that NPs mast cells have distinct phenotypes that vary by tissue location. Glandular mast cells and the diverse subsets of mast cells detected may contribute to the pathogenesis of CRSwNP. PMID:22534535

  17. Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System

    PubMed Central

    Reid, Alicia C.; Brazin, Jacqueline A.; Morrey, Christopher; Silver, Randi B.; Levi, Roberto

    2012-01-01

    Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local reninangiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation. PMID:22103845

  18. IL-33 exacerbates antigen-induced arthritis by activating mast cells

    PubMed Central

    Xu, Damo; Jiang, Hui-Rong; Kewin, Peter; Li, Yubin; Mu, Rong; Fraser, Alasdair R.; Pitman, Nick; Kurowska-Stolarska, Mariola; McKenzie, Andrew N. J.; McInnes, Iain B.; Liew, Foo Y.

    2008-01-01

    IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor α-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFα, and IFNγ), and antibody production. Conversely, treatment of wild-type (WT) but not ST2−/− mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2−/− mice engrafted with mast cells from WT but not from ST2−/− mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA. PMID:18667700

  19. T cell-mediated modulation of mast cell function: heterotypic adhesion-induced stimulatory or inhibitory effects.

    PubMed

    Mekori, Yoseph A; Hershko, Alon Y

    2012-01-01

    Close physical proximity between mast cells and T cells has been demonstrated in several T cell mediated inflammatory processes such as rheumatoid arthritis and sarcoidosis. However, the way by which mast cells are activated in these T cell-mediated immune responses has not been fully elucidated. We have identified and characterized a novel mast cell activation pathway initiated by physical contact with activated T cells, and showed that this pathway is associated with degranulation and cytokine release. The signaling events associated with this pathway of mast cell activation have also been elucidated confirming the activation of the Ras mitogen-activated protein kinase systems. More recently, we hypothesized and demonstrated that mast cells may also be activated by microparticles released from activated T cells that are considered as miniature version of a cell. By extension, microparticles might affect the activity of mast cells, which are usually not in direct contact with T cells at the inflammatory site. Recent works have also focused on the effects of regulatory T cells (Treg) on mast cells. These reports highlighted the importance of the cytokines IL-2 and IL-9, produced by mast cells and T cells, respectively, in obtaining optimal immune suppression. Finally, physical contact, associated by OX40-OX40L engagement has been found to underlie the down-regulatory effects exerted by Treg on mast cell function. PMID:22566892

  20. Inhibitory Effects of Angelica Polysaccharide on Activation of Mast Cells

    PubMed Central

    Mao, Wei-An; Sun, Yuan-Yuan; Mao, Jing-Yi; Wang, Li; Zhang, Jian; Zhou, Jie; Rahman, Khalid; Ye, Ying

    2016-01-01

    This study was designed to investigate the inhibitory effects of Angelica polysaccharide (AP) on activation of mast cells and its possible molecular mechanism. In our study, we determined the proinflammatory cytokines and allergic mediators in anti-DNP IgE stimulated RBL-2H3 cells and found that AP (50, 100, and 200 μg/mL) significantly decreased the release of histamine, β-hexosaminidase, leukotrienes C4 (LTC4), IL-1, IL-4, TNF-α, IL-6, and human monocyte chemotactic protein-1 (MCP-1/CCL2) (p < 0.05). In addition, Ca2+ entry was inhibited by treatment with AP. AP also downregulated the protein expressions of p-Fyn, p-Akt, p-P38, IL-4, TNF-α, and NF-κB p65 in both Fyn gene upregulated and normal RBL-2H3 cells (p < 0.05). Collectively, our results showed that AP could inhibit the activation of mast cells via suppressing the releases of proinflammatory cytokines allergic mediators, Gab2/PI3-K/Akt and Fyn/Syk pathways. PMID:27200102

  1. The architectural relationship of components controlling mast cell endocytosis

    PubMed Central

    Cleyrat, Cédric; Darehshouri, Anza; Anderson, Karen L.; Page, Christopher; Lidke, Diane S.; Volkmann, Niels; Hanein, Dorit; Wilson, Bridget S.

    2013-01-01

    Summary Eukaryotic cells use multiple routes for receptor internalization. Here, we examine the topographical relationships of clathrin-dependent and clathrin-independent endocytic structures on the plasma membranes of leukemia-derived mast cells. The high affinity IgE receptor (FcεRI) utilizes both pathways, whereas transferrin receptor serves as a marker for the classical clathrin-mediated endocytosis pathway. Both receptors were tracked by live-cell imaging in the presence or absence of inhibitors that established their differential dependence on specific endocytic adaptor proteins. The topology of antigen-bound FcεRI, clathrin, dynamin, Arf6 and Eps15-positive structures were analyzed by 2D and 3D immunoelectron microscopy techniques, revealing their remarkable spatial relationships and unique geometry. We conclude that the mast cell plasma membrane has multiple specialized domains for endocytosis. Their close proximity might reflect shared components, such as lipids and adaptor proteins, that facilitate inward membrane curvature. Intersections between these specialized domains might represent sorting stations that direct cargo to specific endocytic pathways. PMID:23986485

  2. Mast cell mediators in the blood of patients with asthma.

    PubMed

    Wasserman, S I

    1985-01-01

    Mast cell activation occurs in allergic asthma and may play a role in a variety of nonallergic asthmatic states. The defined mast cell constituent histamine has been identified in blood of antigen-sensitive challenged asthma patients, while other mediators, whose cell of origin is not fully defined, accompany this amine in blood (Table 1). Due to technical difficulty in accurate assessment, the rapid metabolism of various constituents, and the need for biologic rather than chemical assay of some mediators, it is not yet possible to assess blood constituents for the unequivocal attribution of asthma to activation of a particular cell type. Likewise, the usefulness of blood studies in the prediction of the course of asthma or as serial measurements to define the severity of asthma remains limited. However, it is only with analysis of the appropriate biologic fluids, blood and/or bronchoalveolar lavage materials, that it will be possible to define which potential mediators are, in fact, present and active in asthma. Until such analysis is completed, it is not possible to assign a function in this disease to the numerous potent inflammatory mediators known to be active in in vitro or in vivo models of asthma. PMID:3880526

  3. The putative role of mast cells in lung transplantation.

    PubMed

    Jungraithmayr, W

    2015-03-01

    Mast cells (MCs) were primarily recognized as effector cells of allergy. These cells are acting predominantly at the interface between the host and the external environment, such as skin, gastrointestinal and the respiratory tract. Only recently, MCs have gained increased recognition as cells of functional plasticity with immune-regulatory properties that influence both the innate and the adaptive immune response in inflammatory disorders, cancer and transplantation. Through the secretion of both proinflammatory and antiinflammatory mediators, MCs can either ameliorate or deteriorate the course and outcome in lung transplantation. Recent research from other models recognized the immune-protective activity of MCs including its role as an important source of IL-10 and TGF-β for the modulation of alloreactive T cell responses or assistance in Treg activity. This paper summarizes the current understanding of MCs in lung transplantation and discusses MC-mediated immune-mechanisms by which the outcome of the engrafted organ is modulated. PMID:25693471

  4. Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells.

    PubMed

    Komiyama, Hidenori; Miyake, Koichi; Asai, Kuniya; Mizuno, Kyoichi; Shimada, Takashi

    2014-01-01

    Mast cells are widely distributed in the body and affect their surrounding environment through degranulation and secretion of cytokines. Conversely, mast cells are influenced by environmental stimuli such as cyclical mechanical stretch (CMS), such as that induced by heartbeat and respiration. Peripherally distributed mast cells are surrounded by extracellular matrix, where they bind IgE on their surface by expressing the high-affinity Fc receptor for IgE (FcεRI), and they release mediators after cross-linking of surface-bound IgE by allergen. To analyse how CMS affects mast cell responses, we examined the effect of applying CMS on the behaviour of IgE-bound mast cells (RBL-2H3 cell line) adhering to fibronectin as a substitute for extracellular matrix. We found that CMS enhanced FcεRI-mediated secretion in the presence of antigen (2,4-dinitrophenol-bovine serum albumin). CMS increased expression of IL-4 mRNA and secretion of IL-4 protein. Western blot analysis showed that CMS changes the signal transduction in mitogen-activated protein kinases and AKT, which in turn alters the regulation of IL-4 and increases the secretion of IL-4. These results suggest that CMS modulates the effect of mast cells on inflammation and resultant tissue remodelling. Understanding how CMS affects mast cell responses is crucial for developing therapies to treat mast cell-related diseases. PMID:23584980

  5. Ultraviolet B radiation increases hairless mouse mast cells in a dose-dependent manner and alters distribution of UV-induced mast cell growth factor.

    PubMed

    Kligman, L H; Murphy, G F

    1996-01-01

    In studies of the effects of chronic UVB irradiation on dermal connective tissue in the hairless mouse, we observed that the number and size of mast cells was increased. Because mast cells are known to be associated with connective tissue remodeling, we examined and quantified the effect of increasing UVB (290-320 nm) doses on this cell. Groups of mice were exposed to filtered FS-40 Westinghouse lamps (290-400 nm: peak irradiance 313 nm) for 1-5 minimal erythema doses (MED) thrice weekly for 10 weeks. Appropriate controls were included. Biopsies, processed for light microscopy, were stained with toluidine blue. Mast cells were counted in 15 high-magnification fields per specimen with upper and lower dermis scored separately. Significant increases in large densely granular mast cells occurred at 2 MED in the lower dermis, in association with a UVB-exacerbated granulomatous reaction. In the upper dermis, mast cells were significantly increased with 3 MED. These findings suggest that mast cells may play a dual role in UV-irradiated skin with those in the lower dermis related to inflammation processes and those in the upper dermis involved in connective tissue modeling. To gain understanding of the mechanism of mast cell recruitment and maturation, we examined the effect of UVB on mast cell growth factor expression. This was enhanced in the epidermis by UVB, with a shift from cytoplasmic staining to membrane-associated or intercellular staining at 2 MED and higher. Dermal dendritic and mononuclear cells also showed increased reactivity. PMID:8577864

  6. Differential eosinophil and mast cell regulation: mast cell viability and accumulation in inflammatory tissue are independent of proton-sensing receptor GPR65.

    PubMed

    Zhu, Xiang; Mose, Eucabeth; Hogan, Simon P; Zimmermann, Nives

    2014-06-01

    Extracellular acidification has been observed in allergic inflammatory diseases. Recently, we demonstrated that the proton-sensing receptor G protein-coupled receptor 65 (GPR65) regulates eosinophil survival in an acidic environment in vitro and eosinophil accumulation in an allergic lung inflammation model. For mast cells, another inflammatory cell type critical for allergic responses, it remains unknown whether GPR65 is expressed and/or regulates mast cell viability. Thus, in the present study, we employed in vitro experiments and an intestinal anaphylaxis model in which both mastocytosis and eosinophilia can be observed, particularly in the gastrointestinal tract, to enable us to directly compare the effect of GPR65 expression on these two cell types. We identified GPR65 expression on mast cells; however, unlike eosinophil viability, mast cell viability in vitro is not affected by acidification or GPR65 expression. Mechanistically, we determined that mast cells do not respond to extracellular acidification with increased cAMP levels. Furthermore, in the intestinal anaphylaxis model, we observed a significant reduction of eosinophils (59.1 ± 9.2% decrease) in the jejunum of allergen-challenged GPR65-deficient mice compared with allergen-challenged wild-type mice, despite the degree of antigen sensitization and the expression levels of Th2 cytokines (Il4, Il13) and eosinophil chemokines (Ccl11, Ccl24) in the jejunum being comparable. In contrast, the accumulation of mast cells in allergen-challenged mice was not affected by GPR65 deficiency. In conclusion, our study demonstrates differential regulation of eosinophils and mast cells in inflammatory tissue, with mast cell viability and accumulation being independent of GPR65. PMID:24742990

  7. Differential eosinophil and mast cell regulation: Mast cell viability and accumulation in inflammatory tissue are independent of proton-sensing receptor GPR65

    PubMed Central

    Zhu, Xiang; Mose, Eucabeth; Hogan, Simon P.

    2014-01-01

    Extracellular acidification has been observed in allergic inflammatory diseases. Recently, we demonstrated that the proton-sensing receptor G protein-coupled receptor 65 (GPR65) regulates eosinophil survival in an acidic environment in vitro and eosinophil accumulation in an allergic lung inflammation model. For mast cells, another inflammatory cell type critical for allergic responses, it remains unknown whether GPR65 is expressed and/or regulates mast cell viability. Thus, in the present study, we employed in vitro experiments and an intestinal anaphylaxis model in which both mastocytosis and eosinophilia can be observed, particularly in the gastrointestinal tract, to enable us to directly compare the effect of GPR65 expression on these two cell types. We identified GPR65 expression on mast cells; however, unlike eosinophil viability, mast cell viability in vitro is not affected by acidification or GPR65 expression. Mechanistically, we determined that mast cells do not respond to extracellular acidification with increased cAMP levels. Furthermore, in the intestinal anaphylaxis model, we observed a significant reduction of eosinophils (59.1 ± 9.2% decrease) in the jejunum of allergen-challenged GPR65-deficient mice compared with allergen-challenged wild-type mice, despite the degree of antigen sensitization and the expression levels of Th2 cytokines (Il4, Il13) and eosinophil chemokines (Ccl11, Ccl24) in the jejunum being comparable. In contrast, the accumulation of mast cells in allergen-challenged mice was not affected by GPR65 deficiency. In conclusion, our study demonstrates differential regulation of eosinophils and mast cells in inflammatory tissue, with mast cell viability and accumulation being independent of GPR65. PMID:24742990

  8. Antibacterial agent triclosan suppresses RBL-2H3 mast cell function

    SciTech Connect

    Palmer, Rachel K.; Hutchinson, Lee M.; Burpee, Benjamin T.; Tupper, Emily J.; Pelletier, Jonathan H.; Kormendy, Zsolt; Hopke, Alex R.; Malay, Ethan T.; Evans, Brieana L.; Velez, Alejandro; Gosse, Julie A.

    2012-01-01

    Triclosan is a broad-spectrum antibacterial agent, which has been shown previously to alleviate human allergic skin disease. The purpose of this study was to investigate the hypothesis that the mechanism of this action of triclosan is, in part, due to effects on mast cell function. Mast cells play important roles in allergy, asthma, parasite defense, and carcinogenesis. In response to various stimuli, mast cells degranulate, releasing allergic mediators such as histamine. In order to investigate the potential anti-inflammatory effect of triclosan on mast cells, we monitored the level of degranulation in a mast cell model, rat basophilic leukemia cells, clone 2H3. Having functional homology to human mast cells, as well as a very well defined signaling pathway leading to degranulation, this cell line has been widely used to gain insight into mast-cell driven allergic disorders in humans. Using a fluorescent microplate assay, we determined that triclosan strongly dampened the release of granules from activated rat mast cells starting at 2 μM treatment, with dose-responsive suppression through 30 μM. These concentrations were found to be non-cytotoxic. The inhibition was found to persist when early signaling events (such as IgE receptor aggregation and tyrosine phosphorylation) were bypassed by using calcium ionophore stimulation, indicating that the target for triclosan in this pathway is likely downstream of the calcium signaling event. Triclosan also strongly suppressed F-actin remodeling and cell membrane ruffling, a physiological process that accompanies degranulation. Our finding that triclosan inhibits mast cell function may explain the clinical data mentioned above and supports the use of triclosan or a mechanistically similar compound as a topical treatment for allergic skin disease, such as eczema. -- Highlights: ►The effects of triclosan on mast cell function using a murine mast cell model. ►Triclosan strongly inhibits degranulation of mast cells.

  9. Pycnogenol inhibits immunoglobulin E-mediated allergic response in mast cells.

    PubMed

    Choi, Yun Ho; Yan, Guang Hai

    2009-12-01

    IgE-dependent mast cell activation is known to be associated with the allergic diseases. Pycnogenol (PYC) is a standardized extract of the bark of French maritime pine containing bioflavonoids with a potent antioxidant activity. The antiallergic activity of PYC was evaluated using both in vivo and in vitro experimental models. Oral administration of PYC significantly inhibited anti-dinitrophenyl (DNP) IgE-mediated passive cutaneous anaphylaxis in rats. In an in vitro study, PYC dose-dependently reduced histamine release from rat peritoneal mast cells (RPMC) triggered by anti-DNP IgE. PYC inhibited the protein expression and secretion of tumor necrosis factor-alpha and interleukin-6 in anti-DNP IgE-stimulated RPMC. Moreover, PYC decreased anti-DNP IgE-induced calcium uptake into RPMC. Furthermore, PYC suppressed nuclear factor-kappa B activation. From these results, the clinical use of PYC in the mast cell-mediated immediate-type allergic diseases is proposed. PMID:19441014

  10. Mast cells and histamine alter intestinal permeability during malaria parasite infection.

    PubMed

    Potts, Rashaun A; Tiffany, Caitlin M; Pakpour, Nazzy; Lokken, Kristen L; Tiffany, Connor R; Cheung, Kong; Tsolis, Renée M; Luckhart, Shirley

    2016-03-01

    Co-infections with malaria and non-typhoidal Salmonella serotypes (NTS) can present as life-threatening bacteremia, in contrast to self-resolving NTS diarrhea in healthy individuals. In previous work with our mouse model of malaria/NTS co-infection, we showed increased gut mastocytosis and increased ileal and plasma histamine levels that were temporally associated with increased gut permeability and bacterial translocation. Here, we report that gut mastocytosis and elevated plasma histamine are also associated with malaria in an animal model of falciparum malaria, suggesting a broader host distribution of this biology. In support of mast cell function in this phenotype, malaria/NTS co-infection in mast cell-deficient mice was associated with a reduction in gut permeability and bacteremia. Further, antihistamine treatment reduced bacterial translocation and gut permeability in mice with malaria, suggesting a contribution of mast cell-derived histamine to GI pathology and enhanced risk of bacteremia during malaria/NTS co-infection. PMID:26626201

  11. Anti-allergic effects of Lycopus lucidus on mast cell-mediated allergy model

    SciTech Connect

    Shin, Tae-Yong . E-mail: tyshin@woosuk.ac.kr; Kim, Sang-Hyun; Suk, Kyoungho; Ha, Jeoung-Hee; Kim, InKyeom; Lee, Maan-Gee; Jun, Chang-Duk; Kim, Sang-Yong; Lim, Jong-Pil; Eun, Jae-Soon; Shin, Hye-Young; Kim, Hyung-Min

    2005-12-15

    The current study characterizes the mechanism by which the aqueous extract of Lycopus lucidus Turcz. (Labiatae) (LAE) decreases mast cell-mediated immediate-type allergic reaction. The immediate-type allergic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. LAE has been used as a traditional medicine in Korea and is known to have an anti-inflammatory effect. However, its specific mechanism of action is still unknown. LAE was anally administered to mice for high and fast absorption. LAE inhibited compound 48/80-induced systemic reactions in mice. LAE decreased the local allergic reaction, passive cutaneous anaphylaxis, activated by anti-dinitrophenyl (DNP) IgE antibody. LAE dose-dependently reduced histamine release from rat peritoneal mast cells activated by compound 48/80 or anti-DNP IgE. Furthermore, LAE decreased the secretion of TNF-{alpha} and IL-6 in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-stimulated human mast cells. The inhibitory effect of LAE on the pro-inflammatory cytokine was p38 mitogen-activated protein kinase (MAPK) and nuclear factor-{kappa}B (NF-{kappa}B) dependent. LAE attenuated PMA plus A23187-induced degradation of I{kappa}B{alpha} and nuclear translocation of NF-{kappa}B, and specifically blocked activation of p38 MAPK, but not that of c-jun N-terminal kinase and extracellular signal-regulated kinase. Our findings provide evidence that LAE inhibits mast cell-derived immediate-type allergic reactions and involvement of pro-inflammatory cytokines, p38 MAPK, and NF-{kappa}B in these effects.

  12. Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

    PubMed Central

    Zhang, Lei; Song, Jun; Hou, Xiaohua

    2016-01-01

    Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder since it lacks demonstrable pathological abnormalities. However, in recent years, low grade inflammatory infiltration, often rich in mast cells, in both the small and large bowel, has been observed in some patients with IBS. The close association of mast cells with major intestinal functions, such as epithelial secretion and permeability, neuroimmune interactions, visceral sensation, and peristalsis, makes researchers and gastroenterologists to focus attention on the key roles of mast cells in the pathogenesis of IBS. Numerous studies have been carried out to identify the mechanisms in the development, infiltration, activation, and degranulation of intestinal mast cells, as well as the actions of mast cells in the processes of mucosal barrier disruption, mucosal immune dysregulation, visceral hypersensitivity, dysmotility, and local and central stress in IBS. Moreover, therapies targeting mast cells, such as mast cell stabilizers (cromoglycate and ketotifen) and antagonists of histamine and serotonin receptors, have been tried in IBS patients, and have partially exhibited considerable efficacy. This review focuses on recent advances in the role of mast cells in IBS, with particular emphasis on bridging experimental data with clinical therapeutics for IBS patients. PMID:26755686

  13. The Role of Mast Cell Specific Chymases and Tryptases in Tumor Angiogenesis

    PubMed Central

    de Souza Junior, Devandir Antonio; Santana, Ana Carolina; da Silva, Elaine Zayas Marcelino; Oliver, Constance; Jamur, Maria Celia

    2015-01-01

    An association between mast cells and tumor angiogenesis is known to exist, but the exact role that mast cells play in this process is still unclear. It is thought that the mediators released by mast cells are important in neovascularization. However, it is not known how individual mediators are involved in this process. The major constituents of mast cell secretory granules are the mast cell specific proteases chymase, tryptase, and carboxypeptidase A3. Several previous studies aimed to understand the way in which specific mast cell granule constituents act to induce tumor angiogenesis. A body of evidence indicates that mast cell proteases are the pivotal players in inducing tumor angiogenesis. In this review, the likely mechanisms by which tryptase and chymase can act directly or indirectly to induce tumor angiogenesis are discussed. Finally, information presented here in this review indicates that mast cell proteases significantly influence angiogenesis thus affecting tumor growth and progression. This also suggests that these proteases could serve as novel therapeutic targets for the treatment of various types of cancer. PMID:26146612

  14. Effect of sulfur mustard on mast cells in hairless guinea pig skin

    SciTech Connect

    Graham, J.S.; Bryant, M.A.; Braue, E.H.

    1993-05-13

    The skin of 24 anesthetized hairless guinea pigs was exposed to saturated sulfur mustard (bis-2-chloroethyl sulfide; HD) for 5 and 7 minutes using 14-mm diameter vapor cups. Animals were euthanatized 24 hours after exposure and skin specimens taken for morphometric evaluation of granulated mast cells with an image analysis system (IAS). Tissue specimens were processed in paraffin, sectioned at 5 microns and stained with Unna's stain for mast cells. The number of granulated mast cells and the area occupied by mast cell granules was determined. There were significantly fewer mast cells (p < 0.05) in either HD exposure group than in sham-exposed animals, with significantly fewer mast cells in the 7-minute than the 5-minute HD group. There were also significantly smaller areas occupied by granules in either HD exposure group than in sham-exposed animals. HD-induced lesions in the hairless guinea pig have shown signs of an inflammatory response, and with their granules of vasoactive histamine, mast cells might be expected to play a role in HD-induced injury. Changes in mast cells exposed to low sulfur mustard levels, as detected by an IAS, may serve as an early marker for cutaneous damage, which might not be as easily determined with routine light microscopy.

  15. Proliferation of protease-enriched mast cells in sarcoptic skin lesions of raccoon dogs.

    PubMed

    Noviana, D; W Harjanti, D; Otsuka, Y; Horii, Y

    2004-07-01

    Skin sites, tongue, lung, liver, jejunum and rectum from two raccoon dogs with Sarcoptes scabiei infestation and five normal (control) raccoon dogs were examined in terms of the distribution, proteoglycan properties and protease activity of mast cells. Infestation with S. scabiei caused a significant increase in the number of dermal mast cells. While the number of mast cells (average +/- standard deviation) in specimens of skin from the dorsum, dorsal neck, dorsal hind foot and dorsal fore foot was 40.0 +/- 19.8/mm2 in control animals, it was 236.1 +/- 58.9/mm2 in the skin of mange-infested animals. Histochemical analysis revealed the glycosaminoglycan, heparin, within the mast cells of all organs examined in both control and affected animals. Enzyme-histochemical detection of serine proteases demonstrated an increase in mast-cell-specific protease activity (i.e., chymase and tryptase) in the skin of infested animals. The percentage of mast cells demonstrating chymase activity was 53.0 +/- 27.4% in control animals and 73.8 +/- 19.4% in mite-infested animals. The corresponding results for tryptase activity were 53.5 +/- 25.2% and 89.4 +/- 9.8%. Increases in mast cell chymase or tryptase activity, or both, were also observed within other organs of the infected animals, but the total number of mast cells found at such sites (with the exception of liver and ventrolateral pinna) did not differ from those of control animals. PMID:15144797

  16. Mast cell-derived neurotrophin 4 mediates allergen-induced airway hyperinnervation in early life

    PubMed Central

    Patel, Kruti R.; Aven, Linh; Shao, Fengzhi; Krishnamoorthy, Nandini; Duvall, Melody G.; Levy, Bruce D.; Ai, Xingbin

    2016-01-01

    Asthma often progresses from early episodes of insults. How early life events connect to long-term airway dysfunction remains poorly understood. We demonstrated previously that increased neurotrophin 4 (NT4) levels following early life allergen exposure cause persistent changes in airway smooth muscle (ASM) innervation and airway hyper-reactivity (AHR) in mice. Herein, we identify pulmonary mast cells as a key source of aberrant NT4 expression following early insults. NT4 is selectively expressed by ASM and mast cells in mice, nonhuman primates and humans. We show in mice that mast cell-derived NT4 is dispensable for ASM innervation during development. However, upon insults, mast cells expand in number and degranulate to release NT4 and thus become the major source of NT4 under pathological condition. Adoptive transfer of wild type mast cells, but not NT4−/− mast cells restores ASM hyperinnervation and AHR in KitW-sh/W-sh mice following early life insults. Notably, an infant nonhuman primate model of asthma also exhibits ASM hyperinnervation associated with the expansion and degranulation of mast cells. Together, these findings identify an essential role of mast cells in mediating ASM hyperinnervation following early life insults by producing NT4. This role may be evolutionarily conserved in linking early insults to long-term airway dysfunction. PMID:26860818

  17. Systemic mastocytosis presenting as cardiac tamponade with CD25(+) pericardial mast cells.

    PubMed

    Sukrithan, Vineeth K; Salamon, Jason N; Berulava, Giorgi; Sibinga, Nicholas E; Verma, Amit

    2016-03-01

    In this first-in-literature case, we describe a patient with Systemic mastocytosis presenting with life-threatening cardiac tamponade associated with the presence of aberrant mast cells in the pericardium. Procedures involving surgical incisions through the pericardium in such cases can lead to uncontrolled mast cell degranulation leading to circulatory collapse. PMID:27014452

  18. Influence of Physicochemical Properties of Silver Nanoparticles on Mast Cell Activation and Degranulation

    PubMed Central

    Aldossari, Abdullah A.; Shannahan, Jonathan H.; Podila, Ramakrishna; Brown, Jared M.

    2014-01-01

    Silver nanoparticles (AgNPs) are increasingly being incorporated into products for their antimicrobial properties. This has resulted in increased human exposures and the possibility of adverse health effects. Mast cells orchestrate allergic immune responses through degranulation and release of pre-formed mediators. Little data exists on understanding interactions of AgNPs with mast cells and the properties that influence activation and degranulation. Using bone marrow-derived mast cells and AgNPs of varying physicochemical properties we tested the hypothesis that AgNP physicochemical properties influence mast cell degranulation and osteopontin production. AgNPs evaluated included spherical 20 nm and 110 nm suspended in either polyvinylpyrrolidone (PVP) or citrate, Ag plates suspended in PVP of diameters between 40–60 nm or 100–130 nm, and Ag nanowires suspended in PVP with thicknesses <100 nm and length up to 2 microns. Mast cell responses were found to be dependent on the physicochemical properties of the AgNP. Further, we determined a role for scavenger receptor B1 in AgNP-induced mast cell responses. Mast cell degranulation was not dependent on AgNP dissolution but was prevented by tyrosine kinsase inhibitor pretreatment. This study suggests that exposure to AgNPs may elicit adverse mast cell responses that could contribute to the initiation or exacerbation of allergic disease. PMID:25458489

  19. 3T3 fibroblasts induce cloned interleukin 3-dependent mouse mast cells to resemble connective tissue mast cells in granular constituency

    SciTech Connect

    Dayton, E.T.; Pharr, P.; Ogawa, M.; Serafin, W.E.; Austen, K.F.; Levi-Schaffer, F.; Stevens, R.L.

    1988-01-01

    As assessed by ultrastructure, histochemical staining, and T-cell dependency, in vitro-differentiated interleukin 3-dependent mouse mast cells are comparable to the mast cells that reside in the gastrointestinal mucosa but not in the skin or the serosal cavity of the mouse. The authors now demonstrate that when cloned interleukin 3-dependent mast cells are cocultured with mouse skin-derived 3T3 fibroblasts in the presence of WEHI-3 conditioned medium for 28 days, the mast cells acquire the ability to stain with safranin, increase their histamine content approx. 50-fold and their carboxypeptidase. A content approx. 100-fold, and augment approx. their biosynthesis of proteoglycans bearing /sup 35/S-labeled haparin relative to /sup 35/S-labeled chondroitin sulfate glycosaminoglycans. Thus, fibroblasts induce interleukin 3-dependent mouse mast cells to change phenotype from mucosal-like to connective tissue-like, indicating that the biochemical and functional characteristics of this mast cell type are strongly influenced by the connective tissue microenvironment.

  20. Mast-Cell-Derived TNF Amplifies CD8(+) Dendritic Cell Functionality and CD8(+) T Cell Priming.

    PubMed

    Dudeck, Jan; Ghouse, Shanawaz Mohammed; Lehmann, Christian H K; Hoppe, Anja; Schubert, Nadja; Nedospasov, Sergei A; Dudziak, Diana; Dudeck, Anne

    2015-10-13

    Mast cells are critical promoters of adaptive immunity in the contact hypersensitivity model, but the mechanism of allergen sensitization is poorly understood. Using Mcpt5-CreTNF(FL/FL) mice, we show here that the absence of TNF exclusively in mast cells impaired the expansion of CD8(+) T cells upon sensitization and the T-cell-driven adaptive immune response to elicitation. T cells primed in the absence of mast cell TNF exhibited a diminished efficiency to transfer sensitization to naive recipients. Specifically, mast cell TNF promotes CD8(+) dendritic cell (DC) maturation and migration to draining lymph nodes. The peripherally released mast cell TNF further critically boosts the CD8(+) T-cell-priming efficiency of CD8(+) DCs, thereby linking mast cell effects on T cells to DC modulation. Collectively, our findings identify the distinct potential of mast cell TNF to amplify CD8(+) DC functionality and CD8(+) T-cell-dominated adaptive immunity, which may be of great importance for immunotherapy and vaccination approaches. PMID:26411682

  1. Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans

    PubMed Central

    Asadi, Shahrzad; Sismanopoulos, Nikolaos; Butcher, Alan; Fu, Xueyan; Katsarou-Katsari, Alexandra; Antoniou, Christina; Theoharides, Theoharis C.

    2012-01-01

    Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD2. Que and cromolyn also inhibit histamine, leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption. PMID:22470478

  2. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans.

    PubMed

    Weng, Zuyi; Zhang, Bodi; Asadi, Shahrzad; Sismanopoulos, Nikolaos; Butcher, Alan; Fu, Xueyan; Katsarou-Katsari, Alexandra; Antoniou, Christina; Theoharides, Theoharis C

    2012-01-01

    Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell "stabilizer", is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD(2). Que and cromolyn also inhibit histamine, leukotrienes and PGD(2) from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption. PMID:22470478

  3. Pharmacological treatment options for mast cell activation disease.

    PubMed

    Molderings, Gerhard J; Haenisch, Britta; Brettner, Stefan; Homann, Jürgen; Menzen, Markus; Dumoulin, Franz Ludwig; Panse, Jens; Butterfield, Joseph; Afrin, Lawrence B

    2016-07-01

    Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches. PMID:27132234

  4. Exposure to tobacco-derived materials induces overproduction of secreted proteinases in mast cells

    SciTech Connect

    Small-Howard, Andrea; Turner, Helen . E-mail: hturner@queens.org

    2005-04-15

    Mast cells reside at interfaces with the environment, including the mucosa of the respiratory and gastrointestinal tracts. This localization exposes mast cells to inhaled, or ingested, environmental challenges. In the airways of smokers, resident immune cells will be in contact with the condensed components of cigarette smoke. Mast cells are of particular interest due to their ability to promote airway remodeling and mucus hypersecretion. Clinical data show increased levels of mast cell-secreted tryptase and increased numbers of degranulated mast cells in the lavage and bronchial tissue of smokers. Since mast cell-secreted proteinases (MCPTs), including tryptases, contribute to pathological airway remodeling, we investigated the relationship between mast cell proteinases and smoke exposure. We exposed a mast cell line to cigarette smoke condensate (CSC). We show that CSC exposure increases MCPT levels in mast cells using an assay for tryptase-type MCPT activity. We hypothesized that this increase in MCPT activity reflects a CSC-induced increase in the cytosolic pool of proteinase molecules, via stimulation of MCPT transcription. Transcript array data suggested that mRNA changes in response to CSC were limited in number and peaked after 3 h of CSC exposure. However, we noted marked transcriptional regulation of several MCPT genes. CSC-induced changes in the mRNA levels for MCPTs were confirmed using quantitative RT-PCR. Taken together, our data suggest that chronic exposure to cigarette smoke up-regulates MCPT levels in mast cells at both the protein and the mRNA level. We suggest that the pathological airway remodeling that has been described in clinical studies of smoke inhalation may be attributable to MCPT overproduction in vivo.

  5. Mast cells, disease and gastrointestinal cancer: A comprehensive review of recent findings

    PubMed Central

    Hodges, Kyle; Kennedy, Lindsey; Meng, Fanyin; Alpini, Gianfranco; Francis, Heather

    2012-01-01

    Paul Ehrlich, a German scientist, discovered what is known as the mast cell in the late 1800’s, which has proven to be an important player in the immune system of vertebrates. Mast cells are ubiquitous throughout the tissues of the human body and play numerous roles, both beneficial and destructive. We know they are important in our army of immunity warrior cells, which defend us against viruses, bacteria and parasitic invaders. They are also very well known for the havoc they wreak, causing uncomfortable symptoms due to their release of histamine and other mediators which cause the all too familiar itching, sneezing, urticaria and rhinorrhea of allergic responses. Mast cell activities are diverse and include painful inflammatory reactions in autoimmune conditions such as rheumatoid arthritis. In the gastrointestinal system, mast cells are implicated in diverse actions such as increased gastric acid secretion, polyp formation and uncomfortable conditions such as Irritable Bowel Syndrome. The role of immunology and mast cells in these areas is intriguing but less well understood than their role in allergic responses. Because mast cells have been implicated in both physiologic as well as pathogenic processes, they have been the subjects of avid study. Review of the current literature on mast cell biology reveals that there are many studies of their presence within the tumor microenvironment and evidence, which supports mast cell influence on tumor angiogenesis, tumor invasion, and immune suppression. The studies reviewed in this article concentrate largely on mast cells in human GI malignancies. This review also provides background information regarding mast cells, such as their origination, their location within the body, how they are activated and how they function as mediators. PMID:22943044

  6. Bone marrow-derived cultured mast cells and peritoneal mast cells as targets of a growth activity secreted by BALB/3T3 fibroblasts

    SciTech Connect

    Jozaki, K.; Kuriu, A.; Hirota, S.; Onoue, H.; Ebi, Y.; Adachi, S.; Ma, J.Y.; Tarui, S.; Kitamura, Y. )

    1991-03-01

    When fibroblast cell lines were cultured in contact with bone marrow-derived cultured mast cells (CMC), both NIH/3T3 and BALB/3T3 cell lines supported the proliferation of CMC. In contrast, when contact between fibroblasts and CMC was prohibited by Biopore membranes or soft agar, only BALB/3T3 fibroblasts supported CMC proliferation, suggesting that BALB/3T3 but not NIH/3T3 cells secreted a significant amount of a mast cell growth activity. Moreover, the BALB/3T3-derived growth activity induced the incorporation of (3H)thymidine by CMC and the clonal growth of peritoneal mast cells in methylcellulose. The mast cell growth activity appeared to be different from interleukin 3 (IL-3) and interleukin 4 (IL-4), because mRNAs for these interleukins were not detectable in BALB/3T3 fibroblasts. Although mast cells are genetically deficient in tissues of W/Wv mice, CMC did develop when bone marrow cells of W/Wv mice were cultured with pokeweed mitogen-stimulated spleen cell-conditioned medium. Because BALB/3T3 fibroblast-conditioned medium (BALB-FCM) did not induce the incorporation of (3H)thymidine by W/Wv CMC, the growth activity in BALB-FCM appeared to be a ligand for the receptor encoded by the W (c-kit) locus. Because CMC and peritoneal mast cells are obtained as homogeneous suspensions rather easily, these cells may be potentially useful as targets for the fibroblast-derived mast cell growth activity.

  7. Global microRNA expression is essential for murine mast cell development in vivo

    PubMed Central

    Oh, Sun Young; Brandal, Stephanie; Kapur, Reuben; Zhu, Zhou; Takemoto, Clifford M.

    2014-01-01

    microRNAs (miRNAs) are small, non-coding RNAs that have been shown to play a critical role in normal physiology and disease, such as hematopoietic development and cancer. However, their role in mast cell function and development is poorly understood. The major objective of this study was to determine how global miRNA expression affects mast cell physiology. The RNase III endonuclease, Dicer, is required for the processing of pre-miRNAs into mature miRNAs. To investigate the effect of global miRNA depletion on mast cells in vivo, we generated a mast cell-specific knock out of Dicer in mice. Transgenic mice (Mcpt5-Cre) that express Cre selectively in connective tissue mast cells were crossed with mice carrying the floxed conditional Dicer allele (Dicer fl/fl). Mcpt5-Cre x Dicer fl/fl mice with homozygous Dicer gene deletion in mast cells were found to have a profound mast cell deficiency with near complete loss of peritoneal, gastrointestinal, and skin mast cells. We examined the in vivo functional consequence of mast cell-specific Dicer deletion using an IgE-dependent passive systemic anaphylaxis (PSA) murine model. IgE sensitized wild type Mcpt5-Cre x Dicer +/+ and heterozygous Mcpt5-Cre x Dicer fl/+ mice show marked hypothermia with antigen; however, homozygous Mcpt5-Cre x Dicer fl/fl mice were completely unresponsive to antigen challenge. These studies suggest a critical role for Dicer and miRNA expression for establishment of tissue compartments of functional mast cells in vivo. PMID:25201754

  8. Degradation of C3a anaphylatoxins by rat mast cells

    SciTech Connect

    Fukuoka, Y.; Hugli, T.E.

    1986-05-01

    Incubation of /sup 125/I-human C3a with rat peritoneal mast cells (RMC) causes extensive degradation of the ligand. Both cell-bound and free /sup 125/I-C3a (hu) was degraded by RMC, even at 0/sup 0/C, based on SDS-PAGE analysis. The authors examined several protease inhibitors for their ability to prevent degradation of /sup 125/I-C3a (hu). Degradation of /sup 125/I-C3a (hu) by RMC was not inhibited by leupeptin, antipain, elastatinal, pepstatin, ..cap alpha../sub 1/-antitrypsin or EDTA. TPCK and TLCK were only partially effective. PMSF, chymostatin and SBTI were most effective in preventing /sup 125/I-C3a (hu) degradation. These latter compounds are effective inhibitors of the chymotrypsin-like enzyme chymase extracted from RMC, as is TPCK, based on hydrolysis of the substrate BTEE. Degradation of cell-bound ligand is totally prevented only by PMSF (or DFP). Therefore, /sup 125/I-C3a (hu) bound to the RMC appears to be degraded predominantly by chymase; however the cell-bound ligand is attacked by other surface proteases. Degradation of rat C3a by RMC was examined. After incubation with RMC, cell-bound and free /sup 125/I-C3a (rat) showed no evidence of degradation with or without inhibitors present. From these results, the authors conclude that chymase may not play a significant role in regulating anaphylatoxin activity. Furthermore, the authors propose that rat C3a is a preferred ligand for identifying receptors on mast cells because of its resistance to proteolysis.

  9. Submucosal mast cells in the gastrointestinal tract are a target of staphylococcal enterotoxin type A.

    PubMed

    Ono, Hisaya K; Nishizawa, Masato; Yamamoto, Yoshio; Hu, Dong-Liang; Nakane, Akio; Shinagawa, Kunihiro; Omoe, Katsuhiko

    2012-04-01

    Staphylococcal enterotoxin A (SEA) is a leading causative toxin of staphylococcal food poisoning. However, it remains unclear how this toxin induces emesis in humans, primates, and certain experimental animals. To understand the mechanism of SEA-induced emesis, we investigated the behavior of SEA in the gastrointestinal (GI) tract in vivo using the house musk shrew (Suncus murinus). Immunofluorescence of GI sections showed that perorally administered SEA translocated from the lumen to the interior tissues of the GI tract and rapidly accumulated in certain submucosa cells. These SEA-binding cells in the submucosa were both tryptase- and FcεRIα-positive, suggesting these SEA-binding cells were mast cells. These SEA-binding mast cells were 5-hydroxytryptamine (5-HT)-positive, but the intensity of the 5-HT signal decreased over time compared to that of mast cells in the negative control. Furthermore, toluidine blue staining showed the number of metachromatic mast cells was decreased in the duodenal submucosa, suggesting that SEA binding induced degranulation and release of 5-HT from submucosal mast cells. These observations suggest that the target cells of SEA are submucosal mast cells in the GI tract and that 5-HT released from submucosal mast cells plays an important role in SEA-induced emesis. PMID:22211567

  10. Mast Cell-Mediated Inhibition of Abdominal Neutrophil Inflammation by a PEGylated TLR7 Ligand

    PubMed Central

    Hayashi, Tomoko; Yao, Shiyin; Crain, Brian; Chan, Michael; Cottam, Howard B.; Lao, Fitzgerald; Carson, Dennis A.; Corr, Maripat

    2012-01-01

    Although the mechanisms for sustained chemokine gradients and recurring cell infiltration in sterile peritonitis have not been elucidated, toll-like receptors (TLRs) have been implicated. To abate the deleterious recruitment of neutrophils in sterile inflammation, we repeatedly administered a TLR7 ligand that hyposensitized to TLR7 and receptors that converged on the MyD88-signaling intermediary and reduced cellular infiltration in murine autoimmune models of multiple sclerosis and arthritis. To reduce potential adverse effects, a polyethylene glycol polymer was covalently attached to the parent compound (Tolerimod1). The proinflammatory potency of Tolerimod1 was 10-fold less than the unconjugated TLR7 ligand, and Tolerimod1 reduced neutrophil recruitment in chemically induced peritonitis and colitis. The effects of Tolerimod1 were mediated by the radioresistant cells in radiation chimeric mice and by mast cells in reconstituted mast cell-deficient mice (KitW-sh). Although the Tolerimod1 had weak proinflammatory agonist activity, it effectively reduced neutrophil recruitment in sterile peritoneal inflammation. PMID:22619481