Inhibition of Sphingosine-1-Phosphate-Induced Th17 Cells Ameliorates Alcohol-Associated Steatohepatitis in Mice.
Inhibition of Sphingosine-1-Phosphate-Induced Th17 Cells Ameliorates Alcohol-Associated Steatohepatitis in Mice.
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DOI：
10.1002/hep.31321
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Deng Z
中科院分区：
文献类型：
--
作者：
Chu S;Sun R;Gu X;Chen L;Liu M;Guo H;Ju S;Vatsalya V;Feng W;McClain CJ;Deng Z
长期饮酒伴有肠道炎症。然而，关于肠道免疫系统和鞘脂的改变如何促进酒精性肝病（ALD）的发病机制，我们知之甚少。我们使用WT小鼠、rr γ γt缺陷小鼠、鞘氨醇激酶缺陷小鼠和局部肠道抗炎5-氨基水杨酸（5-ASA）处理的小鼠建立慢性暴饮乙醇喂养模型。靶向脂质组学评估了肠道和肝脏样本中的鞘脂。检查肠道免疫细胞群、鞘脂量和肝损伤水平。结果：酒精摄入诱导肠道免疫细胞群的促炎转变，包括Th17细胞的增加。在rr γt缺陷小鼠中，我们发现Th17细胞是酒精相关肠道炎症和ALD发展所必需的。5-ASA治疗通过抑制CD4+/ rorr γt+/IL-17A+细胞减少酒精性肝损伤和逆转肠道炎症。Th17细胞的增加是由于SK1活性和rorr γt活化的上调。我们发现S1P/S1PR1信号是Th17细胞介导的ALD发展所必需的。重要的是，体内干预阻断S1P/S1PR1信号可显著减轻酒精诱导的肝脏炎症、脂肪变性和损伤。结论：肠道炎症是ALD患者免疫细胞功能的改变。减少肠道Th17细胞可以减少肝损伤。S1P信号以Th17细胞依赖的方式在ALD的发病机制中起关键作用。此外，我们的研究结果表明，局部减少肠道炎症的化合物可能是治疗ALD的独特靶向方法。
Chronic alcohol consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to pathogenesis of alcoholic liver disease (ALD). We used WT mice, RORγt-deficient mice, sphingosine kinase-deficient mice and local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA)-treated mice in a chronic-binge ethanol feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. Results: Alcohol intake induces a pro-inflammatory shift in immune cell populations in the gut, including an increase in Th17 cells. Using RORγt-deficient mice, we found that Th17 cells are required for alcohol-associated gut inflammation and the development of ALD. Treatment with 5-ASA decreases alcohol-induced liver injury and reverses gut inflammation by the suppression of CD4+/RORγt+/IL-17A+ cells. Increased Th17 cells were due to upregulation of SK1 activity and RORγt activation. We found that S1P/S1PR1 signaling are required for the development of Th17 cell-mediated ALD. Importantly, in vivo intervention blocking of S1P/S1PR1 signaling markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Conclusion: Gut inflammation is a functional alteration of immune cells in ALD. Reducing gut Th17 cells leads to reduced liver damage. S1P signaling was crucial in the pathogenesis of ALD in a Th17 cell dependent manner. Furthermore, our findings suggest that compounds that reduce gut inflammation locally may represent a unique targeted approach in the treatment of ALD.
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