OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis
OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis
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OX40 调节先天性和适应性免疫并促进非酒精性脂肪性肝炎。
DOI：
10.1016/j.celrep.2018.12.006
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发表时间：
2018-12-26
期刊：
影响因子：
8.8
通讯作者：
Zhang, Dong
中科院分区：
文献类型：
--
作者：
Sun, Guangyong;Jin, Hua;Zhang, Dong
先天免疫细胞和获得性免疫细胞都参与了非酒精性脂肪性肝炎(NASH)的发病机制，但先天免疫和获得性免疫之间的相互作用在很大程度上是未知的。在这里，我们表明，与WT小鼠相比，OX40(-/-)小鼠在喂食诱发NASH的饮食后，肝脏脂肪堆积、小叶炎症和灶性坏死灶减少。从机制上讲，OX40缺乏抑制Th1和Th17的分化，而T细胞中OX40缺乏抑制单核细胞迁移、抗原呈递和M1极化。可溶性OX40单独刺激可上调肝单核细胞的抗原提呈、趋化因子受体表达和促炎细胞因子的分泌。此外，血浆可溶性OX40水平与人类NASH呈正相关，这表明该发现与临床相关。综上所述，我们揭示了T细胞调节先天免疫细胞的机制。OX40是肝内天然免疫和获得性免疫的关键调节因子，产生双向信号，促进促炎单核细胞、巨噬细胞和T细胞功能，导致NASH的发生。
Both innate and adaptive immune cells are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the crosstalk between innate and adaptive immunity is largely unknown. Here we show that compared with WT mice, OX40(-/-) mice exhibit decreased liver fat accumulation, lobular inflammation, and focal necrosis after feeding with diets that induce NASH. Mechanistically, OX40 deficiency suppresses Th1 and Th17 differentiation, and OX40 deficiency in T cells inhibits monocyte migration, antigen presentation, and M1 polarization. Soluble OX40 stimulation alone upregulates antigen presentation, chemokine receptor expression, and proinflammatory cytokine secretion by liver monocytes. Furthermore, plasma soluble OX40 levels are positively associated with NASH in humans, suggesting clinical relevance of the findings. In conclusion, we show a mechanism for T cell regulation of innate immune cells. OX40 is a key regulator of both intrahepatic innate and adaptive immunity, generates two-way signals, and promotes both proinflammatory monocyte and macrophage and T cell function, resulting in NASH development.