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

Yi Rang Na; Daun Jung; Michelle Stakenborg; Hyeri Jang; Gyo Jeong Gu; Mi Reu Jeong; Soo Youn Suh; Hak Jae Kim; Yoon Hey Kwon; Tae Sik Sung; Seung Bum Ryoo; Kyu Joo Park; Jong Pil Im; Ji Yong Park; Yun Sang Lee; Heonjong Han; Boyoun Park; Sungwook Lee; Daesik Kim; Ho Su Lee; Isabelle Cleynen; Gianluca Matteoli; Seung Hyeok Seok

doi:10.1136/gutjnl-2020-322146

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

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

Authors

Yi Rang Na^{1

2}, Daun Jung¹, Michelle Stakenborg³, Hyeri Jang¹, Gyo Jeong Gu¹, Mi Reu Jeong¹, Soo Youn Suh⁴, Hak Jae Kim⁵, Yoon Hey Kwon⁶, Tae Sik Sung⁷, Seung Bum Ryoo⁸, Kyu Joo Park⁹, Jong Pil Im¹⁰, Ji Yong Park¹¹, Yun Sang Lee¹¹, Heonjong Han^{12

13}, Boyoun Park¹², Sungwook Lee¹³, Daesik Kim¹⁴, Ho Su Lee¹⁵, Isabelle Cleynen¹⁶, Gianluca Matteoli¹⁷, Seung Hyeok Seok¹⁸

Affiliations

¹ Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
² Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea.
³ Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium.
⁴ Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
⁵ Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea.
⁶ Department of Surgery, Emergency Medical Center, Seoul National University Hospital, Seoul, Republic of Korea.
⁷ Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁸ Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁹ Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea.
¹⁰ Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹¹ Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
¹² Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
¹³ Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
¹⁴ Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
¹⁵ Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
¹⁶ Department of Human Genetics, KU Leuven, Leuven, Belgium.
¹⁷ Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium gianluca.matteoli@kuleuven.be lamseok@snu.ac.kr.
¹⁸ Department of Microbiology and Immunology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea gianluca.matteoli@kuleuven.be lamseok@snu.ac.kr.

PMID: 33558271
DOI: 10.1136/gutjnl-2020-322146

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 Ptger4^fl/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 Ptger4^fl/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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Chemokine CXCL1 / metabolism
Disease Models, Animal
Inflammatory Bowel Diseases / metabolism*
Intestinal Mucosa / cytology*
Intestinal Mucosa / metabolism*
Macrophage Activation*
Mice
Receptors, Prostaglandin E, EP4 Subtype / metabolism*
Regeneration
Signal Transduction

Substances

Chemokine CXCL1
Cxcl1 protein, mouse
Ptger4 protein, mouse
Receptors, Prostaglandin E, EP4 Subtype