G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation.
G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation.
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DOI：
10.1097/mib.0000000000000375
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发表时间：
2015-06
影响因子：
4.9
通讯作者：
Rogler G
中科院分区：
文献类型：
--
作者：
de Vallière C;Wang Y;Eloranta JJ;Vidal S;Clay I;Spalinger MR;Tcymbarevich I;Terhalle A;Ludwig MG;Suply T;Fried M;Kullak-Ublick GA;Frey-Wagner I;Scharl M;Seuwen K;Wagner CA;Rogler G
文章于2015年4月7日首次在线发表。
文中有补充数字内容。
一个新的质子感应G蛋白偶联受体家族，包括OGR1、GPR4和TDAG8，被确定对生理pH稳态和炎症具有重要作用。因此，我们确定了质子感应OGR1在肠黏膜中的功能。
在对照组和炎症性肠病（IBD）患者中研究了结肠组织中OGR1的表达。通过实时定量PCR在Mono Mac 6（MM6）细胞系以及原代人源和鼠源单核细胞中研究了细胞激活时OGR1的表达。Ogr1基因敲除小鼠与白细胞介素 - 10（Il - 10）缺陷小鼠杂交，并进行了200多天的研究。使用Ogr1 - / - 和Ogr1 + / +（野生型，WT）腹腔常驻巨噬细胞进行了基因芯片分析。
IBD患者黏膜中OGR1的表达水平高于非IBD对照组。用肿瘤坏死因子（TNF）处理MM6细胞，导致OGR1表达显著上调，这种上调可被核因子 - κB（NF - κB）抑制剂逆转。卡普兰 - 迈耶生存分析显示，雌性Ogr1 - / - / Il - 10 - / - 小鼠直肠脱垂的发病和进展显著延迟。这些小鼠直肠脱垂的情况明显更少。在小鼠巨噬细胞中，由OGR1介导的对细胞外酸化的基因表达上调在炎症和免疫反应、肌动蛋白细胞骨架以及细胞黏附基因通路中富集。
TNF诱导人巨噬细胞系细胞和原代人单核细胞中OGR1的表达。NF - κB抑制可逆转TNF对OGR1表达的诱导作用。在白细胞介素 - 10基因敲除模型中，OGR1缺乏可防止自发性炎症。我们的数据表明，pH感应受体OGR1在黏膜炎症的发病机制中具有病理生理作用。
Article first published online 7 April 2015. Supplemental Digital Content is Available in the Text. A novel family of proton-sensing G protein-coupled receptors, including OGR1, GPR4, and TDAG8, was identified to be important for physiological pH homeostasis and inflammation. Thus, we determined the function of proton-sensing OGR1 in the intestinal mucosa. OGR1 expression in colonic tissues was investigated in controls and patients with IBD. Expression of OGR1 upon cell activation was studied in the Mono Mac 6 (MM6) cell line and primary human and murine monocytes by real-time PCR. Ogr1 knockout mice were crossbred with Il-10 deficient mice and studied for more than 200 days. Microarray profiling was performed using Ogr1−/− and Ogr1+/+ (WT) residential peritoneal macrophages. Patients with IBD expressed higher levels of OGR1 in the mucosa than non-IBD controls. Treatment of MM6 cells with TNF, led to significant upregulation of OGR1 expression, which could be reversed by the presence of NF-κB inhibitors. Kaplan–Meier survival analysis showed a significantly delayed onset and progression of rectal prolapse in female Ogr1−/−/Il-10−/− mice. These mice displayed significantly less rectal prolapses. Upregulation of gene expression, mediated by OGR1, in response to extracellular acidification in mouse macrophages was enriched for inflammation and immune response, actin cytoskeleton, and cell-adhesion gene pathways. OGR1 expression is induced in cells of human macrophage lineage and primary human monocytes by TNF. NF-κB inhibition reverses the induction of OGR1 expression by TNF. OGR1 deficiency protects from spontaneous inflammation in the Il-10 knockout model. Our data indicate a pathophysiological role for pH-sensing receptor OGR1 during the pathogenesis of mucosal inflammation.