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

Abstract

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.

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

“…Following intraperitoneal injection of the bacteria Klebsiella pneumoniae, mMCP-6-deficient mice exhibited both reduced neutrophil recruitment into the peritoneal cavity and significantly increased mortality 32 . A deficiency in mMCP-6 (or in IgE) was also associated with markedly reduced recruitment of eosinophils to the sites of larvae deposition in skeletal muscle during the chronic phase of Trichinella spiralis infection, but was not associated with a detectable abnormality in the intestinal expulsion of the parasite 33 . Recent evidence suggests that mMCP-2 can contribute to neutrophil recruitment and host survival during CLP, but that, in wild-type mice, mast-cell production of intra-cellular IL-15 ordinarily limits the mast cell's ability to produce this protease in that setting 76 .…”

“…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 .…”

“…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.…”

“…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 . Many of these studies also demonstrated that the lack of mast cells 54,[57][58][59][60][61][62][63][64]67,69,70 or a specific mast-cell product 28,32,33,54,60,63,67,68,70 also reduced the pathology associated with the immune response or impaired its effectiveness in promoting host resistance to infection.…”

Essential role for mast cell tryptase in acute experimental colitis

“…However, the corresponding MCs in WT C57BL/6 (B6) mice lack mMCP-7 because of an exon 2/intron 2 splice-site mutation in its gene (4). Using homologous recombination approaches, we created transgenic B6 mouse lines that lack mMCP-6 but express mMCP-7 (designated hereafter as "6 − /7 + B6 mice") or lack both tetramer-forming tryptases (designated hereafter as "6 − /7 − B6 mice") (5,6). We previously showed that mMCP-6-deficient animals were unable to combat bacterial and helminth infections efficiently relative to WT B6 (6 + /7 − ) and WT BALB/c (6 + /7 + ) mice.…”