Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α

Abstract

Although mast cells have been implicated in a variety of inflammatory conditions including immediate hypersensitivity and interstitial cystitis, their physiological role in the body is unknown. We investigated the role of mast cells in host defence against bacterial infections using a well characterized mast-cell-deficiency mouse model. We report here that mast cells, which are selectively located at portals of bacterial entry, are important to host defence. Mast-cell-deficient WBB6F1-W/Wv mice (W/Wv) were up to 20-fold less efficient in clearing enterobacteria than control WBB6F1 +/+ (+/+) mice or mast-cell-reconstituted W/Wv (W/Wv+MC) mice. With higher bacteria inocula, only W/Wv mice died (80%). The limited bacterial clearance in W/Wv mice directly correlated with impaired neutrophil influx. The mast-cell chemoattractant TNF-alpha was implicated in the neutrophil response because TNF-alpha was locally released only in +/+ and W/Wv+MC mice, TNF-alpha-specific antibodies blocked over 70% of the neutrophil influx, and purified mast cells released TNF-alpha upon incubation with bacteria. Additionally, the type-1 fimbrial subunit, FimH, was the necessary enterobacterial component for mast-cell activation and neutrophil influx because an isogenic FimH- mutant evoked a limited neutrophil response in +/+ mice compared to wild-type bacteria.

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.…”

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…Although the dermal cells responsible for recruiting neutrophils following UVB exposure are not known, studies using mast cell deficient mice show that mast cells are critical cellular intermediaries required for the recruitment of neutrophils to sites of inflammation. 84 While direct exposure of cord blood derived mast cells to UVB in vitro causes CXCL8 production in these cells, 85 this is unlikely to be the primary mechanism by which dermal mast cells produce CXCL8 after UV exposure in vivo; rather, we hypothesize that UVB-induced PAF stimulates IL-33 production in fibroblasts that then acts either in an autocrine manner 86 or on neighboring dermal mast cells 23 to induce expression of neutrophil chemoattractants such as CXCL8. In this way, UV-induced IL-33 acts as a novel endogenous danger signal mediating the recruitment of innate immune cells to sites of infection or cellular damage.…”

Identification of novel mast cell genes by serial analysis of gene expression in cord blood‐derived mast cells

“…MCs release newly generated mediators such as PGD 2 , leukotriene (LT) B 4 or LTC 4 upon activation as well as preformed mediators [3]. We found the tags for enzymes relating to synthesis and degradation of PGD 2 appeared frequently (Table 2), while those involved in synthesizing lipoxygenase products such as LTB 4 or LTC 4 were detected rarely (5-lipoxygenase, zero; LTC 4 synthase, one; and LTA 4 hydrolase, one). This suggests a possibility that PGD 2 is constitutively synthesized and may have some functions in unstimulated MCs.…”

“…Recent ¢ndings suggest that MCs are also involved in non-allergic processes such as innate immunity by producing high levels of cytokines [4]. However little is known about other roles of MCs.…”