Critical protective role of mast cells in a model of acute septic peritonitis

Abstract

Mast cells play a detrimental role in IgE-dependent allergic reactions. In contrast, a protective function for mast cells has been proposed on the basis of some worm infection models. No reports exist on the in vivo significance of these cells in bacterial infections. Here we use congenitally mast-cell-deficient W/Wv mice and normal +/+ littermates to analyse the role of mast cells in a model of acute septic peritonitis (caecum ligation and puncture (CLP)). Following CLP, W/Wv mice showed a significantly increased mortality compared to +/+ mice. The selective reconstitution of W/Wv mice with cultured +/+ mast cells substantially protected them from the lethal effects of CLP, whereas an anti-tumor-necrosis-factor (TNF) antibody injected immediately after CLP completely suppressed this protection. Our results reveal a previously unrecognized protective role of mast cells and mast-cell-derived TNF in acute bacterial peritonitis.

gp49B1 suppresses stem cell factor‐induced mast cell activation‐secretion and attendant inflammation in vivo

“…The ability of gp49B1 to suppress the mast cell response to activating concentrations of soluble SCF is consistent with the biologic necessity for mast cells to respond fully to the basal concentrations of SCF that mediate their development and survival in vivo [21] so as to provide intact cells that protect against bacterial infections [22][23][24][25][26]. The hyperresponsive phenotype in gp49B -/-mice was not the result of an abnormal level of endogenous SCF, because naïve gp49B -/-mice had normal numbers of mast cells not only in the ear [4], but also in the tongue, heart, lung, and small intestine (data not shown), indicating that the SCF-dependent, systemic development of mast cells is not negatively regulated by gp49B1.…”

“…The cytokine stem cell factor (SCF) is mandatory for normal mast cell development; mice of the WBB6F1-Kit W /Kit W-v strain that have a dysfunctional form of the SCF receptor (c-kit) have essentially no tissue mast cells [21]. These mice are more susceptible to death when subjected to a microbial challenge such as acute septic peritonitis, but they can be protected by adoptive transfer of normal mast cells, an effect that is enhanced when mast cell development in vivo is amplified by provision of exogenous SCF [22][23][24][25][26]. Thus, SCF produced by both stromal and hematopoietic cells [27] provides a host resistance function that is mediated through maintenance of mast cell numbers in peripheral tissues.…”

Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin

“…[30][31][32] The observation that BMMC secrete gzmB and that rgzmB induces disintegration of EC-cell-cell contacts at concentrations where gross morphological changes and EC detachment are not yet observed (3 mg/ml), may indicate that mast cell-derived gzmB contributes to the recruitment of leukocytes by facilitating their transendothelial migration. 33 Evidence that intraperitoneal administration of mMCP-6 results in neutrophil infiltration into the peritoneum 27 supports the idea of a general role for mast cell-derived proteases in leukocyte recruitment.…”

Oxidative stress stimulates IL‐4 and IL‐6 production in mast cells by an APE/Ref‐1‐dependent pathway

“…It is now clear that this view was too limited as we have begun to appreciate the function of mast cells in innate immunity and a possible role in autoimmune disease [8,9]. Mast cels are multifunctional, tissue-dwelling cells [20] and a potential source of proinflammatory cytokines and chemotactic mediators [21] which are decisive in initiating the immune and inflammatory responses. Despite the fact that IgE/Ag binding to mast cells is the primary stimulus for activating mast cell degranulation and cytokine production, it is clear that IgE-independent stimuli can activate these cells and induce inflammation [22][23][24].…”