The Mast Cell-restricted Tryptase mMCP-6 Has a Critical Immunoprotective Role in Bacterial Infections

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2007; 282(29):20809-15. DOI: 10.1074/jbc.M611842200
Source: PubMed


Although it has been shown that mast cell-deficient mice have diminished innate immune responses against bacteria, the most important immunoprotective factors secreted from activated mast cells have not been identified. Mouse mast cell protease 6 is a tetramer-forming tryptase. This serine protease is abundant in the secretory granules and is exocytosed upon bacterial challenge. Here we have described the generation of a mast cell protease-6-null mouse. Our discovery that mice lacking this neutral protease cannot efficiently clear Klebsiella pneumoniae from their peritoneal cavities reveals an essential role for this serine protease, and presumably its human ortholog, in innate immunity.

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    • "MC deficient mice pretreated with human tryptase defend themselves more effectively against intratracheally delivered Klebsiella pneumoniae [11]. mMCP-6-deficient-mice are less able to clear Klebsiella pneumonia injected in the peritoneal cavity due to less of recruitment of neutrophils [12]. "
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    ABSTRACT: Human mast cells (MCs) are a rich reservoir of neutral proteases, packed in large amounts in their granules and comprising a high fraction of all cellular proteins. Among these proteases, tryptase is involved in angiogenesis after their release from activated MC granules, as it has been demonstrated in different in vitro and in vivo assays. Moreover, tryptase-positive MCs increase in number and vascularization increases in a linear fashion in different solid and hematological tumors. This complex interplay between MCs and tumor angiogenesis have led to consider the therapeutic use of angiogenesis inhibitors, which specifically target the angiogenic activity of tryptase, such as gabexate mesilate and nafamostat mesilate, two inhibitors of trypsin-like serine proteases. Copyright © 2014. Published by Elsevier Inc.
    Experimental Cell Research 12/2014; 332(2). DOI:10.1016/j.yexcr.2014.11.014 · 3.25 Impact Factor
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    • "This interaction inhibits mast cell degranulation and calcium mobilization without affecting cytokine secretion, thus reducing the amplitude of immediate hypersensitivity responses (Gri et al. 2008; Piconese et al. 2009; Frossi et al. 2011). Mast cell proteases also contribute to immune tolerance in that they reduce antigenicity and leukocyte recruitment through cleavage of antigens, toxic peptides, cytokines, and chemotactic factors (Mellon et al. 2002; Pang et al. 2006; Rauter et al. 2006; Thakurdas et al. 2007; Rauter et al. 2008 ; Waern et al. 2009). Even though histamine is generally viewed as a proinflammatory mediator , its binding to hista - mine receptor 2 ( H2R) mediates immune suppression as seen in mast cell - dependent , H2R - dependent immune sup 2009 ). "
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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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    • "To address these deficiencies, a number of inbred C57BL/6 mouse lines have been created using homologous recombination approaches in which a single gene was disrupted in most instances. Confirming the importance of MC tryptases in immunity and inflammation, transgenic C57BL/6 mice that lack the tetramer-forming tryptases mMCP-6 and mMCP-7 had a diminished ability to recruit neutrophils into their bacteria-infected peritoneal cavities (Thakurdas et al., 2007), arthritic joints (McNeil et al., 2008; Shin et al., 2009), and inflamed colons (Hamilton et al., 2011) and lungs (Beckett et al., 2013) relative to WT mice. The fact that mice and human MCs express three tryptases that have overlapping substrate specificities contributed to the lack of appreciation of these neutral proteases in different diseases. "
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    ABSTRACT: Mast cells (MCs) are active participants in blood coagulation and innate and acquired immunity. This review focuses on the development of mouse and human MCs, as well as the involvement of their granule serine proteases in inflammation and the connective tissue remodeling that occurs during the different phases of the healing process of wounded skin and other organs. The accumulated data suggest that MCs, their tryptases, and their chymases play important roles in tissue repair. While MCs initially promote healing, they can be detrimental if they are chronically stimulated or if too many MCs become activated at the same time. The possibility that MCs and their granule serine proteases contribute to the formation of keloid and hypertrophic scars makes them potential targets for therapeutic intervention in the repair of damaged skin.
    Advances in Immunology 02/2014; 122:211-52. DOI:10.1016/B978-0-12-800267-4.00006-7 · 5.96 Impact Factor
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