Nucleotide-binding oligomerization domain-containing protein 2 controls host response to Campylobacter jejuni in Il10-/- mice

Abstract

Innate signaling-induced antimicrobial response represents a key protective host feature against infectious microorganisms such as Campylobacter species. In this study, we investigated the role of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in Campylobacter jejuni-induced intestinal inflammation. Specific-pathogen-free Il10-/-, Nod2-/-, and Il10-/-; Nod2-/- mice were infected with C. jejuni (109 colonyforming units/mouse) 24 hours after a 7-day course of antibiotic treatment. Three weeks later, host responses were determined. The nitric oxide (NO) donor sodium nitroprusside was injected intraperitoneally (2 mg/kg daily) to supplement NO. Although healthy in specific-pathogen-free conditions, Il10-/-; Nod2-/- mice developed severe intestinal inflammation following C. jejuni infection, compared with Nod2-/- and Il10-/- mice. The onset of colitis was associated with elevated neutrophil accumulation, crypt abscesses, and expression of the endogenous proinflammatory mediators Il-1β, Tnfà, and Cxcl1. Fluorescence in situ hybridization and culture assay showed enhanced C. jejuni invasion into the colon and mesenteric lymph nodes in Il10-/-; Nod2-/- mice, compared with Il10-/- mice. C. jejuni-induced bactericidal NO production was reduced in peritoneal macrophages from Il10-/-; Nod2-/- mice, compared with Il10-/- mice. Importantly, sodium nitroprusside attenuated C. jejuni-induced colitis in Il10-/-; Nod2-/- mice. Our findings suggest that NOD2 signaling is critical to control campylobacteriosis in Il10-/- mice, a process involving NOD2-mediated bactericidal responses.