GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis.
GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis.
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DOI：
10.4049/jimmunol.1700604
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
Manicassamy S
中科院分区：
文献类型：
--
作者：
Ranganathan P;Shanmugam A;Swafford D;Suryawanshi A;Bhattacharjee P;Hussein MS;Koni PA;Prasad PD;Kurago ZB;Thangaraju M;Ganapathy V;Manicassamy S
在诸如肠的粘膜部位，免疫系统对入侵的病原体发起强有力的免疫，同时保持对肠道植物群和摄入的食物抗原的耐受状态。这种现象背后的分子机制仍然知之甚少。在这里，我们报告说，GPR 81，乳酸受体，在结肠DC和巨噬细胞的信号在抑制结肠炎症和恢复结肠稳态中起着重要作用。小鼠中GPR 81基因缺失导致Th 1/Th 17细胞分化增加和调节性T细胞分化减少，导致对结肠炎症的易感性增强。这是由于缺乏GPR 81的肠道APC产生促炎细胞因子（IL-6、IL-1β和TNF-α）增加以及免疫调节因子（IL-10、RA和IDO）表达减少。与这些发现一致，GPR 81的药理学活化降低了炎性细胞因子的表达并改善了结肠炎症。总之，这些发现确定了GPR 81信号通路在调节免疫耐受和结肠炎症中的新的重要作用。因此，GPR 81通路的操纵可以为增强调节反应和治疗结肠炎症提供新的机会。
At mucosal sites such as the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food antigens. The molecular mechanisms underlying this phenomenon remain poorly understood. Here, we report that signaling by GPR81, a receptor for lactate, in colonic DCs and macrophages plays an important role in suppressing colonic inflammation and restoring colonic homeostasis. Genetic deletion of GPR81 in mice led to increased Th1/Th17 cell differentiation and reduced regulatory T cell differentiation, resulting in enhanced susceptibility to colonic inflammation. This was due to increased production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and decreased expression of immune regulatory factors (IL-10, RA and IDO) by intestinal APCs lacking GPR81. Consistent with these findings, pharmacological activation of GPR81 decreased inflammatory cytokine expression and ameliorated colonic inflammation. Taken together, these findings identify a new and important role for the GPR81 signaling pathway in regulating immune tolerance and colonic inflammation. Thus, manipulation of the GPR81 pathway could provide novel opportunities for enhancing regulatory responses and treating colonic inflammation.
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DOI：
10.1097/mco.0b013e32833b648e
发表时间：
2010-09
影响因子：
3.1
作者：
Bassaganya-Riera J;Hontecillas R
通讯作者：
Hontecillas R
影响因子：
5.4
作者：
De Calisto, Jaime;Villablanca, Eduardo J.;Mora, J. Rodrigo
通讯作者：
Mora, J. Rodrigo
影响因子：
5.4
作者：
Grygiel-Górniak B
通讯作者：
Grygiel-Górniak B
影响因子：
3.7
作者：
Errea A;Cayet D;Marchetti P;Tang C;Kluza J;Offermanns S;Sirard JC;Rumbo M
通讯作者：
Rumbo M
影响因子：
4.8
作者：
Jeninga, Ellen H.;Bugge, Anne;Kalkhoven, Eric
通讯作者：
Kalkhoven, Eric