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.
- inflammatory bowel disease
- epithelial barrier
- epithelial differentiation
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YRN and DJ are joint first authors.
GM and SHS are joint senior authors.
Contributors YRN, GM and SHS conceptualised this study. YRN and DJ designed the experiments. YRN, HRJ, DJ, GJG, MRJ, SYS, MS and JYP performed the experiments. YRN, DJ, HJH, BP, SL, HSL and IC analysed data. YRN and DJ interpreted data. DK, HJK, YHK, TSS, SBR, KJP, JPI and Y-SL provided vital reagents. YRN, DJ, MS, GM and SHS contributed to data analysis and writing of the manuscript.
Funding SHS was supported by the Basic Science Research ProgramProgramme through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2020R1A2C2010202). YRN was supported by the NRF (NRF-2017R1D1A1B04031161) and the SNUH Research Fund (4320200020). DK was supported by KRIBB Research Initiative ProgramProgramme (KG-20200023). MS was supported by a PhD fellowship from the FWO-Research Foundation—Flanders (1186317N). GM was supported by the FWO grants G0D8317N, G0A7919N, and S008419N, a grant from the International OrganizationOrganisation for the Study of Inflammatory Bowel Diseases (IOIBD), a grant from the European Crohns and Colitis OrganizationOrganisation (ECCO) and grants from the KU Leuven Internal Funds (C12/15/016 and C14/17/097). Collaboration between SHS and GM laboratories is supported by cooperation grants between FWO and NRF (vs03917N, vs07220N and 2019K2A9A1A06099778).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval Human clinical samples were obtained from the Seoul National University Hospital after approval by the institutional review board (H-1104-066-358). Patient information is provided in online supplemental table S1. Animal experiments were conducted in accordance with the Institute for Experimental Animal College of Medicine and performed according to the Guidelines for the Care and Use of Laboratory Animals by the Institutional Animal Care and Use Committee of Seoul National University (SNU-171016-1-2) and by the Animal Care and Animal Experiments Committee of KU Leuven (091/2016).
Data availability statement 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.
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