Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation
| العنوان: | Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation |
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| المؤلفون: | Sungwook Lee, Kyu Joo Park, Gyo Jeong Gu, Tae Sik Sung, Ji Yong Park, Daesik Kim, Gianluca Matteoli, Mi Reu Jeong, Hyeri Jang, Soo Youn Suh, Ho Su Lee, Yun Sang Lee, Daun Jung, Seung Bum Ryoo, Jong Pil Im, Isabelle Cleynen, Yoon Hey Kwon, Michelle Stakenborg, Yi Rang Na, Boyoun Park, Heonjong Han, Hak Jae Kim, Seung Hyeok Seok |
| المصدر: | Gut. 70:2249-2260 |
| بيانات النشر: | BMJ, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Chemokine, biology, Chemistry, Prostaglandin E2 receptor, Regeneration (biology), Gastroenterology, Inflammation, medicine.disease, epithelial differentiation, macrophages, prostaglandins, CXCL1, inflammatory bowel disease, medicine, biology.protein, Cancer research, Macrophage, epithelial barrier, medicine.symptom, Colitis, Epithelial cell differentiation |
| الوصف: | ObjectiveDysfunctional 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.DesignWe 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.ResultsHere, 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.ConclusionPTGER4+ 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. |
| وصف الملف: | Print-Electronic |
| تدمد: | 1468-3288 0017-5749 |
| DOI: | 10.1136/gutjnl-2020-322146 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::817f0f9baf5eaa3dbf6b49f728af835e https://doi.org/10.1136/gutjnl-2020-322146 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....817f0f9baf5eaa3dbf6b49f728af835e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14683288 00175749 |
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| DOI: | 10.1136/gutjnl-2020-322146 |