LAUSR

Significance Epithelial antimicrobial defense is an important innate mechanism to maintain intestinal homeostasis and closely involved in the pathogenesis of inflammatory bowel disease (IBD). Chemerin, which is abundantly expressed in barrier tissues, regulates tissue inflammation via CMKLR1, its functional receptor. We herein reveal a role of epithelial chemerin–CMKLR1 signaling in sustaining epithelial antimicrobial defense, thereby conferring protection from microbiota-driven neutrophilic colitis and subsequent tumorigenesis following epithelial injury. Mechanistically, we identify lactoperoxidase (LPO), which is highly expressed in murine colonic epithelium, as the downstream effector of chemerin–CMKLR1 signaling to restrict the outgrowth and invasion of gram-negative bacteria, thereby preventing dysregulated CXCL1/2 production and pathological mucosal neutrophilia. Thus, targeting chemerin–CMKLR1/LPO axis may be beneficial for improving dysbiosis in IBD patients.