Loss of Histochemical Identity in Mast Cells Lacking Carboxypeptidase A

Feyerabend, Thorsten B.; Hausser, Heinz; Tietz, Annette; Blum, Carmen; Hellman, Lars; Straus, Anita H.; Takahashi, Hélio K.; Morgan, Ellen S.; Dvorak, Ann M.; Fehling, Hans Jörg; Rodewald, Hans Reimer

doi:10.1128/mcb.25.14.6199-6210.2005

Cited by 84 publications

(100 citation statements)

References 49 publications

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“…This finding contrasts with some secretory granule proteases whose absence perturbs expression of other constituents of the secretory granule (35,42).…”

Section: Mmcp-6 ϫ/ϫ Micecontrasting

confidence: 52%

Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase ofTrichinella spiralisInfection

Shin

Watts

Oettgen

et al. 2008

The Journal of Immunology

129

110

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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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“…This finding contrasts with some secretory granule proteases whose absence perturbs expression of other constituents of the secretory granule (35,42).…”

Section: Mmcp-6 ϫ/ϫ Micecontrasting

confidence: 52%

Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase ofTrichinella spiralisInfection

Shin

Watts

Oettgen

et al. 2008

The Journal of Immunology

129

110

View full text Add to dashboard Cite

show abstract

“…The expression of carboxypeptidase A, an exopeptidase mediator and major protein component in secretory granules, begins during the mast cell progenitor stage and increases as immature mast cells mature (41,42). Because carboxypeptidase Ϫ/Ϫ mast cells fail to develop a fully mature phenotype, carboxypeptidase may also play an important intracellular function (43). Carboxypeptidase A was found to be overrepresented in the DR lyp/lyp relative to the DR ϩ/ϩ by Ͼ30-fold in both array and qRT-PCR analyses.…”

Section: Qrt-pcr Of Genes Relevant To Mast Cell Functionmentioning

confidence: 88%

Evidence of a Functional Role for Mast Cells in the Development of Type 1 Diabetes Mellitus in the BioBreeding Rat

Geoffrey

Song

Kwitek

et al. 2006

The Journal of Immunology

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Human type 1 diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic β cells and is modeled in many respects by the lymphopenic and spontaneously diabetic BioBreeding (BB) DRlyp/lyp rat. Previously, preonset expression profiling of whole DRlyp/lyp pancreatic lymph nodes (PLN) revealed innate immune activity, specifically that of mast cells and eosinophils. Furthermore, we observed that pancreatic islets of DRlyp/lyp rats as well as those of diabetes-inducible BB DR+/+ rats potentially recruit innate cells through eotaxin expression. Here we determine that lifelong eotaxin expression begins before 40 days of life and is localized specifically to β cells. In this report, we find that PLN mast cells are more abundant in DRlyp/lyp compared with related BB DR+/+ rats (2.1 ± 0.9% vs 0.9 ± 0.4% of total cells, p < 0.0001). DRlyp/lyp PLN mast cell gene expression profiling revealed an activated population and included significant overrepresentation of transcripts for mast cell protease 1, cationic trypsinogen, carboxypeptidase A, IL-5, and phospholipase Cγ. In the DR+/+ rat, which develops T1DM upon depletion of T regulator cells, mast cells displayed gene expression consistent with the negative regulation of degranulation, including significant overrepresentation of transcripts encoding tyrosine phosphatase SHP-1, lipid phosphatase SHIP, and E3 ubiquitin ligase c-Cbl. To recapitulate the negative mast cell regulation observed in the DR+/+ rats, we treated DRlyp/lyp rats with the mast cell “stabilizer” cromolyn, which significantly (p < 0.05) delayed T1DM onset. These findings are consistent with a growing body of evidence in human and animal models, where a role for mast cells in the initiation and progression of autoimmune disease is emerging.

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“…Some of the positive immunomodulatory functions of mast cells that have been proposed based on in vitro studies have been confirmed in vivo using mast cell knock-in mice 1,54,[57][58][59][60][61][62][63][64][65][66][67][68][69][70] or in mice lacking specific mast-cell-associated proteases [26][27][28][32][33][34] or lacking specific protease enzymatic activity 11 (Table 1 ). In many of these studies, the end points assessed included the recruitment of particular immune cells, such as granulocytes 28,32,33,[57][58][59][60][61]63,64,[67][68][69][70] , DCs 62,64,65,71 or various subpopulations of lymphocytes 64,67,70,72 .…”

Section: Positive Immunomodulatory Functions In Vivomentioning

confidence: 93%

“…If that mediator is selectively expressed by mast cells, and if its deletion does not significantly influence the expression of other mastcell products, then it is possible to draw conclusions about the role of that mast-cell product in vivo. For example, mice that lack mouse mast-cell protease-1 (mMCP-1) [26][27][28] , mMCP-4 29,30 , mMCP-6 [31][32][33] , or mouse mast cell-carboxypeptidase A (mMC-CPA) 34 , or that have a mutated mMC-CPA that essentially lacks enzymatic activity 11 , have been used to analyze whether the absence of these proteases (or their enzymatic activity) influences other aspects of the mast-cell phenotype, such as content of other stored mediators, as well as to define the functions of such mast-cell-associated proteases in vivo.…”

Section: Other Approachesmentioning

confidence: 99%

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

2008

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Loss of Histochemical Identity in Mast Cells Lacking Carboxypeptidase A

Cited by 84 publications

References 49 publications

Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase ofTrichinella spiralisInfection

Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase ofTrichinella spiralisInfection

Evidence of a Functional Role for Mast Cells in the Development of Type 1 Diabetes Mellitus in the BioBreeding Rat

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

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