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. 2021 Dec;70(12):2249-2260.
doi: 10.1136/gutjnl-2020-322146. Epub 2021 Feb 7.

Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation

Yi Rang Na  1   2 , Daun Jung  1 , Michelle Stakenborg  3 , Hyeri Jang  1 , Gyo Jeong Gu  1 , Mi Reu Jeong  1 , Soo Youn Suh  4 , Hak Jae Kim  5 , Yoon Hey Kwon  6 , Tae Sik Sung  7 , Seung Bum Ryoo  8 , Kyu Joo Park  9 , Jong Pil Im  10 , Ji Yong Park  11 , Yun Sang Lee  11 , Heonjong Han  12   13 , Boyoun Park  12 , Sungwook Lee  13 , Daesik Kim  14 , Ho Su Lee  15 , Isabelle Cleynen  16 , Gianluca Matteoli  17 , Seung Hyeok Seok  18
Affiliations

Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation

Yi Rang Na et al. Gut. 2021 Dec.

Abstract

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.

Keywords: epithelial barrier; epithelial differentiation; inflammatory bowel disease; macrophages; prostaglandins.

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Conflict of interest statement

Competing interests: None declared.

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