Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling
Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling
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肠道微生物介导的次级胆汁酸通过 TGR5 信号调节树突状细胞以减轻自身免疫性葡萄膜炎
DOI：
10.1016/j.celrep.2021.109726
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发表时间：
2021-09-21
期刊：
影响因子：
8.8
通讯作者：
Li, Hong
中科院分区：
文献类型：
--
作者：
Hu, Jianping;Wang, Chaokui;Li, Hong
肠道微生物介导的次级胆汁酸 (BA) 通过 G 蛋白偶联受体和/或核受体在能量平衡和宿主代谢中发挥重要作用。新的证据表明，BA 对于通过这些受体维持先天免疫反应非常重要。然而，BAs 对自身免疫性葡萄膜炎的作用仍不清楚。在这里，我们证明患有实验性自身免疫性葡萄膜炎 (EAU) 的动物粪便和血清中与微生物群相关的次级 BA 浓度降低。肠道 BA 库的恢复可减轻 EAU 的严重程度，这与树突状细胞 (DC) 中核因子 kappa B (NF-kappa B) 相关促炎细胞因子的抑制有关。 TGR5 缺陷部分逆转了脱氧胆酸 (DCA) 对 DC 的抑制作用。 TGR5 信号传导还通过 DC 中的环 AMP (cAMP)-蛋白激酶 A (PKA) 途径抑制 NF-kappa B 激活。此外，DCA 和 TGR5 激动剂均可抑制人单核细胞来源的 DC 激活。综上所述，我们的结果表明 BA 代谢在适应性免疫反应中发挥重要作用，并且可能是自身免疫性葡萄膜炎的治疗靶点。
Gut microbiota-mediated secondary bile acids (BAs) play an important role in energy balance and host metabolism via G protein-coupled receptors and/or nuclear receptors. Emerging evidence suggests that BAs are important for maintaining innate immune responses via these receptors. However, the effect of BAs on autoimmune uveitis is still unknown. Here, we demonstrate decreased microbiota-related secondary BA concentration in feces and serum of animals with experimental autoimmune uveitis (EAU). Restoration of the gut BAs pool attenuates severity of EAU in association with inhibition of nuclear factor kappa B (NF-kappa B)-related pro-inflammatory cytokines in dendritic cells (DCs). TGR5 deficiency partially reverses the inhibitory effect of deoxycholic acid (DCA) on DCs. TGR5 signaling also inhibits NF-kappa B activation via the cyclic AMP (cAMP)-protein kinase A (PKA) pathway in DCs. Additionally, both DCA and TGR5 agonists inhibit human monocyte-derived DC activation. Taken together, our results suggest that BA metabolism plays an important role in adaptive immune responses and might be a therapeutic target in autoimmune uveitis.