Critical role of OX40 in drug-induced acute liver injury
Critical role of OX40 in drug-induced acute liver injury
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OX40 在药物性急性肝损伤中的关键作用
DOI：
10.1111/bph.15041
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发表时间：
2020
影响因子：
7.3
通讯作者：
Dong Zhang
中科院分区：
文献类型：
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作者：
Chunpan Zhang;Hua Jin;Yan Wang;Changying Li;Xinyan Zhao;Yanmeng Li;Wen Shi;Yue Tian;Hufeng Xu;Dan Tian;Kai Liu;Jidong Jia;Guangyong Sun;Dong Zhang
背景与目的先天免疫系统和适应性免疫系统在药物性肝损伤（DILI）中均起重要作用。然而，DILI的先天免疫和适应性免疫之间的相互作用在很大程度上是未知的。广泛的串扰可能是由这些免疫系统之间的共刺激相互作用造成的。OX40是一种共刺激分子，但它是否调节DILI的肝内免疫反应尚不清楚。实验方法采用对乙酰氨基酚（扑热息痛）、四氯化碳（CCl4）和半乳糖胺/脂多糖（GalN/LPS）诱导野生型（WT）和dox40基因敲除（KO）小鼠急性肝损伤，并比较疾病进展。给药后，血浆中OX40水平显著升高，肝内CD4+T细胞中OX40水平升高。与WT小鼠相比，ox40缺失小鼠的肝损伤减轻。与WT小鼠相比，ox40ko小鼠肝脏中Th1、Th17细胞和巨噬细胞的浸润减少。此外，与WT‐CD4+T细胞转移相比，ox40ko‐CD4+T细胞过继移植到ag1−/−小鼠的肝损伤减轻，肝脏巨噬细胞浸润减少，促炎细胞因子分泌减少。此外，体外OX40/Fc刺激表明，可溶性OX40增强了小鼠巨噬细胞的生物学功能，包括上调与炎症和组织浸润相关的基因。最后，与健康对照相比，DILI患者的可溶性OX40水平显著升高。结论与意义sox40是促进促炎巨噬细胞和CD4+T细胞功能，加重扑热息痛诱导的肝损伤的关键分子。OX40可作为DILI的诊断指标和治疗靶点。
Background and PurposeThe innate and adaptive immune systems both play important roles in drug‐induced liver injury (DILI). However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co‐stimulatory interactions between these immune systems. OX40 is a co‐stimulatory molecule, but whether it regulates the intrahepatic immune response in DILI remains unknown.Experimental ApproachAcute liver injury was induced by paracetamol (acetaminophen), carbon tetrachloride (CCl4), andd‐galactosamine/LPS (GalN/LPS) in wild‐type (WT) andOx40knockout (KO) mice, and disease progress was compared.Key ResultsPlasma OX40 levels were significantly increased and were augmented in intrahepatic CD4+T cells after paracetamol, CCl4, or GalN/LPS administration. Liver injury inOx40‐deficient mice was attenuated compared with that in WT mice. Compared with WT mice, hepatic infiltration of Th1 and Th17 cells and macrophages inOx40KO mice was reduced. Furthermore, adoptive transfer ofOx40KO‐CD4+T cells toRag1−/−mice resulted in alleviated liver injury compared with WT‐CD4+T‐cell transfer, with reduced liver infiltration of macrophages and pro‐inflammatory cytokine secretion. Moreover, OX40/Fc stimulation in vitro revealed that soluble OX40 enhanced the biological function of murine macrophages, including up‐regulation of genes associated with inflammation and tissue infiltration. Finally, soluble OX40 levels were significantly elevated in DILI patients compared with healthy controls.Conclusion and ImplicationsOX40 is a key molecule that promotes both pro‐inflammatory macrophage and CD4+T‐cell function, exacerbating paracetamol‐induced liver injury. OX40 could serve as a diagnostic index and therapeutic target of DILI.