MAST-CELL MODULATION OF NEUTROPHIL INFLUX AND BACTERIAL CLEARANCE AT SITES OF INFECTION THROUGH TNF-ALPHA

ALTHOUGH mast cells have been implicated in a variety of inflammatory conditions including immediate hypersensitivity and interstitial cysti tis,(1,2) their physiological role in the body is unknown. We investig ated the role of mast cells in host defence against bacterial infectio ns using a well characterized mast-cell-deficiency mouse model(3,4), W e report here that mast cells, which are selectively located at portal s of bacterial entry, are important to host defence, Mast-cell-deficie nt WBB6F1-W/W-v mice (W/W-v) were up to 20-fold less efficient in clea ring enterobacteria than WBB6F1+/+ (+/+)mice or mast-cell-reconstitute d W/W-v (W/W-v + MC) mice. With higher bacterial inocula, only W/W-v m ice died (80%). The limited bacterial clearance in W/W-v mice directly correlated with impaired neutrophil influx. The mast-fell chemoattrac tant TNF-alpha was implicated in the neutrophil response because TNF-a lpha was locally released only in +/+ and W/W-v + MC mice, TNF-alpha-s pecific antibodies blocked over 70% of the neutrophil influx, and puri fied mast cells released TNF-alpha upon incubation with bacteria, Addi tionally, the type-1 fimbrial subunit, FimH, was the necessary enterob acterial component for mast-cell activation and neutrophil influx beca use an isogenic FimH(-) mutant evoked a limited neutrophil response in +/+ mice compared to wild-type bacteria.