한빛사 논문
Yi Rang Na1,2, Daun Jung1, Michelle Stakenborg3, Hyeri Jang1, Gyo Jeong Gu1, Mi Reu Jeong1, Soo Youn Suh4, Jae Kim5, Yoon Hey Kwon6, Tae Sik Sung7, Seung Bum Ryoo8, Kyu Joo Park9, Jong Pil Im10, Ji Yong Park11, Yun Sang Lee11, Heonjong Han12,13, Boyoun Park12, Sungwook Lee13, Daesik Kim14, Ho Su Lee15, Isabelle Cleynen16, Matteoli3, Seung Hyeok Seok17
1Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
2Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea
3Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
4Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
5Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea
6Department of Surgery, Emergency Medical Center, Seoul National University Hospital, Seoul, Republic of Korea
7Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
8Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
9Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
10Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
11Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea
12Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
13Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea
14Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
15Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea
16Department of Human Genetics, KU Leuven, Leuven, Belgium
17Department of Microbiology and Immunology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
YRN and DJ are joint first authors.
Correspondence to Prof Gianluca Matteoli, Professor Seung Hyeok Seok.
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.
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