The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis
The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis
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DOI：
10.4049/jimmunol.1700183
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发表时间：
2017-07-15
影响因子：
4.4
通讯作者：
Fiorucci, Stefano
中科院分区：
文献类型：
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作者：
Biagioli, Michele;Carino, Adriana;Fiorucci, Stefano
GPBAR 1（TGR 5或M-BAR）是一种G蛋白偶联受体，在单核细胞/巨噬细胞中高度表达。在这项研究中，我们的目的是确定GPBAR 1在介导化学诱导的结肠炎模型中的白细胞运输中的作用，并研究GPBAR 1的小分子激动剂BAR 501的治疗潜力。这些研究表明，GPBAR 1基因消融增强了结肠固有层中经典活化的巨噬细胞的募集，并恶化了炎症的严重程度。相反，在三硝基苯磺酸和恶唑酮模型中，BAR 501激活GPBAR 1通过减少Ly 6C（+）单核细胞从血液到肠粘膜的运输来逆转肠道炎症。暴露于BAR 501使肠巨噬细胞从经典活化的（CD 11b（+），CCR 7（+），F4/80（-））与交替激活的（CD 11b（+），CCR 7（-），F4/80（+））表型，减少炎性基因表达（TNF-α、IFN-γ、IL-1 β、IL-6和CCL 2 mRNA），并减轻消耗综合征和结肠炎的严重程度（结肠炎疾病活动指数降低约70%）。在Gpbar 1（-/-）小鼠中失去保护作用。暴露于BAR 501增加了结肠IL-10和TGF-β mRNA的表达以及CD 4 +/Foxp（3 +）细胞的百分比。BAR 501的有益作用在IL-10（-/-）小鼠中丧失。在巨噬细胞系中，BAR 501对IL-10的调节是GPBAR 1依赖性的，并且通过CREB募集到IL-10启动子中的响应元件来介导。总之，GPBAR 1在循环单核细胞和结肠巨噬细胞中表达，其活化促进IL-10依赖性向替代活化表型的转变。GPBAR 1的靶向可能为炎症性肠病提供治疗选择。
GPBAR1 (TGR5 or M-BAR) is a G protein-coupled receptor for secondary bile acids that is highly expressed in monocytes/ macrophages. In this study, we aimed to determine the role of GPBAR1 in mediating leukocyte trafficking in chemically induced models of colitis and investigate the therapeutic potential of BAR501, a small molecule agonist for GPBAR1. These studies demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation. In contrast, GPBAR1 activation by BAR501 reversed intestinal inflammation in the trinitrobenzenesulfonic acid and oxazolone models by reducing the trafficking of Ly6C (+) monocytes from blood to intestinal mucosa. Exposure to BAR501 shifted intestinal macrophages from a classically activated (CD11b (+), CCR7 (+), F4/80(-)) to an alternatively activated (CD11b (+), CCR7(-), F4/80 (+)) phenotype, reduced the expression of inflammatory genes (TNF-alpha, IFN-gamma, IL-1 beta, IL-6, and CCL2 mRNAs), and attenuated the wasting syndrome and severity of colitis (approximate to 70% reduction in the Colitis Disease Activity Index). The protective effect was lost in Gpbar1 (-/-) mice. Exposure to BAR501 increased the colonic expression of IL-10 and TGF-b mRNAs and the percentage of CD4 +/Foxp(3 +) cells. The beneficial effects of BAR501 were lost in Il-10(-/-) mice. In a macrophage cell line, regulation of IL-10 by BAR501 was GPBAR1 dependent and was mediated by the recruitment of CREB to its responsive element in the IL-10 promoter. In conclusion, GPBAR1 is expressed in circulating monocytes and colonic macrophages, and its activation promotes a IL-10-dependent shift toward an alternatively activated phenotype. The targeting of GPBAR1 may offer therapeutic options in inflammatory bowel diseases.