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Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation
Gut ( IF 23.0 ) Pub Date : 2021-12-01 , DOI: 10.1136/gutjnl-2020-322146
Yi Rang Na 1, 2 , Daun Jung 1 , Michelle Stakenborg 3 , Hyeri Jang 1 , Gyo Jeong Gu 1 , Mi Reu Jeong 1 , Soo Youn Suh 4 , Hak Jae Kim 5 , Yoon Hey Kwon 6 , Tae Sik Sung 7 , Seung Bum Ryoo 8 , Kyu Joo Park 9 , Jong Pil Im 10 , Ji Yong Park 11 , Yun Sang Lee 11 , Heonjong Han 12, 13 , Boyoun Park 12 , Sungwook Lee 13 , Daesik Kim 14 , Ho Su Lee 15 , Isabelle Cleynen 16 , Gianluca Matteoli 17 , Seung Hyeok Seok 18
Affiliation  

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. RNA-seq data are publicly available through the NIH GEO platform (): 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.

中文翻译:

前列腺素 E2 受体 PTGER4 表达巨噬细胞促进炎症后肠上皮屏障再生

目的 肠道炎症的功能失调和黏膜愈合改变是炎症性肠病 (IBD) 发病机制的基本特征。肠道巨噬细胞在炎症消退过程中至关重要,但其粘膜愈合能力的机制仍然难以捉摸。设计 我们研究了前列腺素 E2 (PGE2) 受体 PTGER4 在 IBD 患者和肠道炎症小鼠模型中对肠道巨噬细胞分化的作用。我们研究了葡聚糖硫酸钠 (DSS) 诱导的结肠炎期间 Csf1r-iCre Ptger4fl/fl 小鼠的粘膜愈合和肠上皮屏障再生。研究了 PTGER4+ 巨噬细胞分泌分子对上皮类器官分化的影响。结果在这里,我们描述了在人和小鼠中具有粘膜愈合特性的表达 PTGER4 的肠道巨噬细胞的一个子集。Csf1r-iCre Ptger4fl/fl 小鼠在 DSS 结肠炎模型中表现出有缺陷的黏膜愈合和上皮屏障再生。从机制上讲,增加的 PGE2 黏膜水平会通过丝裂原活化蛋白激酶 (MAPKs) 在单核细胞衍生的 PTGER4+ 巨噬细胞中触发趋化因子 (CXC 基序) 配体 1 (CXCL1) 分泌。CXCL1 在结肠炎期间通过再生隐窝驱动上皮细胞分化和增殖。用装载有 MAPK 激动剂的脂质体对巨噬细胞进行特异性治疗可增强条件性巨噬细胞 PTGER4 缺陷小鼠体内 CXCL1 的产生,恢复其缺陷的上皮再生并有利于粘膜愈合。结论 PTGER4+肠道巨噬细胞对于支持肠道干细胞生态位和受损上皮细胞的再生至关重要。我们的研究结果为开发一类新的治疗靶点铺平了道路,以促进巨噬细胞的愈合功能并有利于 IBD 患者的缓解。RNA-seq 数据可通过 NIH GEO 平台公开获得(): GEO 加入 GSE141093。数据包含在葡聚糖硫酸钠诱导的结肠炎期间来自野生型和 Csf1r-Ptger4-/- 小鼠的肠道巨噬细胞的全基因组转录谱。
更新日期:2021-11-08
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