TY - JOUR T1 - Prostaglandin E<sub>2</sub> receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation JF - Gut JO - Gut SP - 2249 LP - 2260 DO - 10.1136/gutjnl-2020-322146 VL - 70 IS - 12 AU - Yi Rang Na AU - Daun Jung AU - Michelle Stakenborg AU - Hyeri Jang AU - Gyo Jeong Gu AU - Mi Reu Jeong AU - Soo Youn Suh AU - Hak Jae Kim AU - Yoon Hey Kwon AU - Tae Sik Sung AU - Seung Bum Ryoo AU - Kyu Joo Park AU - Jong Pil Im AU - Ji Yong Park AU - Yun Sang Lee AU - Heonjong Han AU - Boyoun Park AU - Sungwook Lee AU - Daesik Kim AU - Ho Su Lee AU - Isabelle Cleynen AU - Gianluca Matteoli AU - Seung Hyeok Seok Y1 - 2021/12/01 UR - http://gut.bmj.com/content/70/12/2249.abstract N2 - Objective Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive.Design We investigated the role of the prostaglandin E2 (PGE2) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. We studied mucosal healing and intestinal epithelial barrier regeneration in Csf1r-iCre Ptger4fl/fl mice during dextran sulfate sodium (DSS)-induced colitis. The effect of PTGER4+ macrophage secreted molecules was investigated on epithelial organoid differentiation.Results Here, we describe a subset of PTGER4-expressing intestinal macrophages with mucosal healing properties both in humans and mice. Csf1r-iCre Ptger4fl/fl mice showed defective mucosal healing and epithelial barrier regeneration in a model of DSS colitis. Mechanistically, an increased mucosal level of PGE2 triggers chemokine (C-X-C motif) ligand 1 (CXCL1) secretion in monocyte-derived PTGER4+ macrophages via mitogen-activated protein kinases (MAPKs). CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during colitis. Specific therapeutic targeting of macrophages with liposomes loaded with an MAPK agonist augmented the production of CXCL1 in vivo in conditional macrophage PTGER4-deficient mice, restoring their defective epithelial regeneration and favouring mucosal healing.Conclusion PTGER4+ intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium. Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favour remission in patients with IBD.RNA-seq data are publicly available through the NIH GEO platform (https://www.ncbi.nlm.nih.gov/geo/): GEO accession GSE141093. The data contain genome-wide transcriptional profiles of intestinal macrophages from wildtype and Csf1r-Ptger4−/− mice during dextran sodium sulfate induced colitis. ER -