Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase of Trichinella spiralis Infection

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2008; 180(7):4885-91. DOI: 10.4049/jimmunol.180.7.4885
Source: PubMed


Although the innate immune function of mast cells in the acute phase of parasitic and bacterial infections is well established, their participation in chronic immune responses to indolent infection remains incompletely understood. In parasitic infection with Trichinella spiralis, the immune response incorporates both lymphocyte and mast cell-dependent effector functions for pathogen eradication. Among the mechanistic insights still unresolved in the reaction to T. spiralis are the means by which mast cells respond to parasites and the mast cell effector functions that contribute to the immunologic response to this pathogen. We hypothesized that mast cell elaboration of tryptase may comprise an important effector component in this response. Indeed, we find that mice deficient in the tryptase mouse mast cell protease-6 (mMCP-6) display a significant difference in their response to T. spiralis larvae in chronically infected skeletal muscle tissue. Mechanistically, this is associated with a profound inability to recruit eosinophils to larvae in mMCP-6-deficient mice. Analysis of IgE-deficient mice demonstrates an identical defect in eosinophil recruitment. These findings establish that mast cell secretion of the tryptase mMCP-6, a function directed by the activity of the adaptive immune system, contributes to eosinophil recruitment to the site of larval infection, thereby comprising an integral link in the chronic immune response to parasitic infection.

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    • "Wild-type (WT) mice and mice lacking serglycin ( Abrink et al. 2004) or the tryptase mMCP-6 (Shin et al. 2008) were on C57BL/6J genetic background. All animal experiments were approved by the local ethical committee (Uppsala, Sweden). "
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    ABSTRACT: Mast cells are known to have a detrimental impact on a variety of pathological conditions. There is therefore an urgent need of developing strategies that limit their harmful effects. The aim of this study was to accomplish this by developing a means of inducing mast cell apoptosis. The strategy was to identify novel compounds that induce mast cell apoptosis by permeabilization of their secretory lysosomes (granules). As a candidate, we assessed mefloquine, an anti-malarial drug that has been proposed to have lysosome-permeabilizing activity. Mefloquine was added to mast cells and administered in vivo, followed by assessment of the extent and mechanisms of mast cell death. Mefloquine was cytotoxic to murine and human mast cells. Mefloquine induced apoptotic cell death of wild-type mast cells whereas cells lacking the granule compounds serglycin proteoglycan or tryptase were shown to undergo necrotic cell death, the latter finding indicating a role of the mast cell granules in mefloquine-induced cell death. In support of this, mefloquine was shown to cause compromised granule integrity and to induce leakage of granule components into the cytosol. Mefloquine-induced cell death was refractory to caspase inhibitors but was completely abrogated by reactive oxygen species inhibition. These findings identify mefloquine as a novel anti-mast cell agent, which induces mast cell death through a granule-mediated pathway. Mefloquine may thus become useful in therapy aiming at limiting harmful effects of mast cells.
    12/2014; 2(6). DOI:10.1002/prp2.66
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    • "Chymases, tryptases , and carboxypeptidase A are exclusively expressed by mast cells. They have been implicated in several pathological states including arthritis, allergic airway inflammation, tumor angiogenesis, innate immune defense, glomerulonephritis , and abdominal aortic aneurism formation (McNeil et al. 2008; Shin et al. 2008; Sun et al. 2009; Waern et al. 2009; Scandiuzzi et al. 2010; Souza-Junior et al. 2011). Chymases can contribute to ECM remodeling both directly, through cleavage of fibronectin and non-helical collagens, and indirectly, through activation of matrix metalloproteinases (MMPs), which are also released upon mast cell activation (Fang et al. 1996; Tchougounova et al. 2005; Caughey 2007). "
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    ABSTRACT: 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.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 07/2014; 62(10). DOI:10.1369/0022155414545334 · 1.39 Impact Factor
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    • "Using mMCP-6 deficient mice, others shows that mMCP-6 acts a proinflammatory mediator to recruit neutrophils to protect against infections25. Shin et al observed that mast cell-derived mMCP-6 was a critical molecule in recruiting eosinophils to expel parasites from the infected sites26. Our results demonstrate that mMCP-6 is also involved in the immune regulation. "
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    ABSTRACT: Although mast cells play a critical role in allergic reactions, the cells are also involved in the protective immunity in the body. This study aims to investigate the role of mast cells in immune regulation during aberrant T helper (Th)2 responses. In this study, an adoptive antigen-specific Th2 response model was established with mast cell-deficient mice to test the role of mast cell in the immune regulation. Cell culture was employed to test the role of mast cells in the modulation of the expression of B cell lymphoma 6 protein (Bcl-6) in Th2 cells. The results showed that after adoptive transfer with immune cells, the mast cell-deficient mice showed stronger Th2 pattern responses in the intestine than that in the mast cell-sufficient mice. Mast cell-derived mouse mast cell protease-6 increased the expression of Bcl-6 in Th2 cells. Bcl-6 inhibited the expression of GATA-3 in Th2 cells, subsequently, forkhead box P3 was increased and the Th2 cytokines were reduced in the cells; the cells thus showed the immune regulatory properties similar to regulatory T cells. We conclude that bedsides initiating immune inflammation, mast cells also contribute to the immune regulation on Th2 polarization.
    Scientific Reports 04/2014; 4:4649. DOI:10.1038/srep04649 · 5.58 Impact Factor
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