A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo.
A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo.
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DOI：
10.1371/journal.pone.0100883
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Modis LK
中科院分区：
文献类型：
--
作者：
Lewis ND;Patnaude LA;Pelletier J;Souza DJ;Lukas SM;King FJ;Hill JD;Stefanopoulos DE;Ryan K;Desai S;Skow D;Kauschke SG;Broermann A;Kuzmich D;Harcken C;Hickey ER;Modis LK
GPBAR 1是一种G蛋白偶联受体，可被某些胆汁酸激活，在胆汁酸合成、脂质代谢和能量稳态调节中发挥重要作用。最近的证据表明，GPBAR 1也可能通过其在单核细胞和巨噬细胞上的表达在减少炎症反应中具有重要作用。为了进一步了解GPBAR 1在炎症中的作用，我们产生了一种新型的、选择性的、专有的GPBAR 1激动剂，并测试了其在体外和体内减少单核细胞和巨噬细胞活化的有效性。我们已经使用这种激动剂，与先前描述的激动剂一起研究GPBAR 1的激动作用，并表明它们都可以在体外诱导cAMP并减少人单核细胞和单核细胞衍生的巨噬细胞中TLR活化诱导的细胞因子产生。此外，通过使用RNA测序（RNA-Seq），我们确定了一组选择的基因，这些基因在LPS激活过程中受到GPBAR 1激动作用的调控。为了进一步确定GPBAR 1在炎症中的体内作用，我们评估了GPBAR 1表达，并在循环小鼠单核细胞上发现了高水平。GPBAR 1的激动作用降低了小鼠单核细胞中LPS诱导的细胞因子产生和体内血清细胞因子水平。GPBAR 1的激动作用在多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中也具有深远的影响，其中单核细胞起重要作用。用GPBAR 1激动剂处理的小鼠表现出EAE临床评分的显著降低，这与单核细胞和小胶质细胞活化减少以及单核细胞和T细胞向CNS的运输减少相关。这些数据证实了GPBAR 1在体内控制单核细胞和巨噬细胞活化中的重要性，并支持了GPBAR 1的选择性激动剂在治疗炎性疾病中的基本原理。
GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.