The NLRP3 inflammasome mediates DSS-induced intestinal inflammationin Nod2 knockout mice

摘要

Crohn’s disease (CD) is a chronic disorder of the gastrointestinal tractcharacterized by inflammation and intestinal epithelial injury. Loss of functionmutations in the intracellular bacterial sensor NOD2 are major risk factors forthe development of CD. In the absence of robust bacterial recognition by NOD2 aninflammatory cascade is initiated through alternative PRRs leading to CD. In thepresent study, MCC950, a specific small molecule inhibitor of NLR pyrindomain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate(DSS)-induced intestinal inflammation in mice. NLRP3 inflammasome formation was observed at a higher rate inNOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3complex formation led to an increase in IL-1β secretion in both the smallintestine and colon of ko mice. This increase in IL-1βsecretion in the intestine was attenuated by MCC950 leading to decreased diseaseseverity in ko mice. Our work suggests that NLRP3inflammasome activation may be a key driver of intestinal inflammation in theabsence of functional NOD2. NLRP3 pathway inhibition can prevent intestinalinflammation in the absence of robust NOD2 signaling.