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,^1,2 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^3,4. 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/W^v mice (W/W^v) were up to 20-fold less efficient in clearing enterobacteria than control WBB6F1+/+ (+/+) mice or mast-cell-reconstituted W/W^v (W/W^v + MC) mice. With higher bacterial inocula, only W/W^v mice died (80%). The limited bacterial clearance in W/W^v mice directly correlated with impaired neutrophil influx. The mast-cell chemoattractant TNF-α was implicated in the neutrophil response because TNF-α was locally released only in +/+ and W/W^v + MC mice, TNF-α-specific antibodies blocked over 70% of the neutrophil influx, and purified mast cells released TNF-α 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.