| First Author | Lin Y | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 29 | Pages | e2205574119 |
| PubMed ID | 35858331 | Mgi Jnum | J:332524 |
| Mgi Id | MGI:7427342 | Doi | 10.1073/pnas.2205574119 |
| Citation | Lin Y, et al. (2022) Epithelial chemerin-CMKLR1 signaling restricts microbiota-driven colonic neutrophilia and tumorigenesis by up-regulating lactoperoxidase. Proc Natl Acad Sci U S A 119(29):e2205574119 |
| abstractText | Intestinal barrier immunity is essential for controlling gut microbiota without eliciting harmful immune responses, while its defect contributes to the breakdown of intestinal homeostasis and colitis development. Chemerin, which is abundantly expressed in barrier tissues, has been demonstrated to regulate tissue inflammation via CMKLR1, its functional receptor. Several studies have reported the association between increased expression of chemerin-CMKLR1 and disease severity and immunotherapy resistance in inflammatory bowel disease (IBD) patients. However, the pathophysiological role of endogenous chemerin-CMKLR1 signaling in intestinal homeostasis remains elusive. We herein demonstrated that deficiency of chemerin or intestinal epithelial cell (IEC)-specific CMKLR1 conferred high susceptibility to microbiota-driven neutrophilic colon inflammation and subsequent tumorigenesis in mice following epithelial injury. Unexpectedly, we found that lack of chemerin-CMKLR1 signaling specifically reduced expression of lactoperoxidase (LPO), a peroxidase that is predominantly expressed in colonic ECs and utilizes H(2)O(2) to oxidize thiocyanates to the antibiotic compound, thereby leading to the outgrowth and mucosal invasion of gram-negative bacteria and dysregulated CXCL1/2-mediated neutrophilia. Importantly, decreased LPO expression was causally linked to aggravated microbiota-driven colitis and associated tumorigenesis, as LPO supplementation could completely rescue such phenotypes in mice deficient in epithelial chemerin-CMKLR1 signaling. Moreover, epithelial chemerin-CMKLR1 signaling is necessary for early host defense against bacterial infection in an LPO-dependent manner. Collectively, our study reveals that the chemerin-CMKLR1/LPO axis represents an unrecognized immune mechanism that potentiates epithelial antimicrobial defense and restricts harmful colonic neutrophilia and suggests that LPO supplementation may be beneficial for microbiota dysbiosis in IBD patients with a defective innate antimicrobial mechanism. |
