Neutrophil elastase regulates both type 1 and type 2 immune responses to enteric infection (MPF1P.800)

Local neutrophil influx occurs in response to enteric bacterial as well as nematode infection. Neutrophilic release of the serine protease, elastase (NE), is implicated in host defense as well as tissue injury. The aim of this study was to determine the contribution of elastase in host defense against enteric pathogens that induce a Th1/Th17 or a Th2 immune response. Elastase deficient (ELA1-/-) or C57BL/6 (WT) mice (n=5-7) were inoculated with Nippostrongylus brasiliensis (Nb) and studied 5 and 9 days later or infected with Citrobacter rodentium (Cr) and studied 14 days later. Gene expression was determined by real-time PCR in samples of small intestine or colon. Nb infection in WT mice induced a 21-fold STAT6-dependent increase in elastase expression. ELA1-/- mice had accelerated Nb expulsion coupled with significantly (p<0.01) augmented elevation in IL-4, IL-13, and M2 marker (e.g arginase-1) expression when compared to WT mice. Both strains showed similar increases in smooth muscle hypercontractility and epithelial permeability. In contrast, ELA1-/- mice had delayed clearance of Cr infection with impaired upregulation of IFNγ and IL-17A expression when compared to WT mice. These data indicate that during nematode infection, the upregulation of elastase negatively regulates the Th2 response and could be a novel target for modulating type 2 immunity. During bacterial infection, elastase is essential for the upregulation of type 1 cytokines and pathogen clearance in the gut.