Article Text

Download PDFPDF
Original research
Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation
  1. Yi Rang Na1,2,
  2. Daun Jung1,
  3. Michelle Stakenborg3,
  4. Hyeri Jang1,
  5. Gyo Jeong Gu1,
  6. Mi Reu Jeong1,
  7. Soo Youn Suh4,
  8. Hak Jae Kim5,
  9. Yoon Hey Kwon6,
  10. Tae Sik Sung7,
  11. Seung Bum Ryoo8,
  12. Kyu Joo Park9,
  13. Jong Pil Im10,
  14. Ji Yong Park11,
  15. Yun Sang Lee11,
  16. Heonjong Han12,13,
  17. Boyoun Park12,
  18. Sungwook Lee13,
  19. Daesik Kim14,
  20. Ho Su Lee15,
  21. Isabelle Cleynen16,
  22. Gianluca Matteoli3,
  23. Seung Hyeok Seok17
  1. 1Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
  2. 2Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea
  3. 3Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
  4. 4Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
  5. 5Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea
  6. 6Department of Surgery, Emergency Medical Center, Seoul National University Hospital, Seoul, Republic of Korea
  7. 7Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
  8. 8Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
  9. 9Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
  10. 10Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
  11. 11Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea
  12. 12Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
  13. 13Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea
  14. 14Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
  15. 15Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea
  16. 16Department of Human Genetics, KU Leuven, Leuven, Belgium
  17. 17Department of Microbiology and Immunology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
  1. Correspondence to Prof Gianluca Matteoli, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium; gianluca.matteoli{at}kuleuven.be; Professor Seung Hyeok Seok, Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea; lamseok{at}snu.ac.kr

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.

  • inflammatory bowel disease
  • macrophages
  • prostaglandins
  • epithelial barrier
  • epithelial differentiation

Statistics from Altmetric.com

Footnotes

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.