Hepatic interferon regulatory factor 8 expression mediates liver ischemia/reperfusion injury in mice.
Hepatic interferon regulatory factor 8 expression mediates liver ischemia/reperfusion injury in mice.
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DOI：
10.1016/j.bcp.2021.114728
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发表时间：
2021-08
影响因子：
5.8
通讯作者：
Guangjiang Shi;Zixuan Zhang;Shuqian Ma;Yan Li;Shijia Du;Ya Chu;Yuan Li;Xinying Tang
中科院分区：
文献类型：
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作者：
Guangjiang Shi;Zixuan Zhang;Shuqian Ma;Yan Li;Shijia Du;Ya Chu;Yuan Li;Xinying Tang
肝缺血再灌注（I/R）损伤是肝移植术后不可避免的并发症。肝脏缺血到再灌注损伤的过程伴随着代谢异常、库普弗细胞活化、中性粒细胞募集和细胞因子的释放。据报道，几种干扰素调节因子（irf）的激活可增强或限制I/R损伤进展，但IRF8在I/R损伤进展中的调节作用尚不清楚。在本研究中，我们使用过表达的肝脏IRF8和敲除小鼠来探索IRF8在I/ r介导的肝损伤中的功能。根据我们的研究结果，与对照组小鼠不同，IRF8基因敲除小鼠的炎症细胞浸润、炎症细胞因子释放和血清天冬氨酸转氨酶/丙氨酸转氨酶水平显著降低，从而改善了I/R后的坏死损伤。相反，IRF8在WT小鼠中的过表达明显加重了肝脏结构损伤及其功能异常。我们进一步发现irf8介导的炎症细胞浸润部分依赖于I/R期间的早期自噬和NF-κΒ信号通路。自噬抑制剂羟氯喹和NF-κΒ信号通路抑制剂secukinumab预处理AAV8-IRF8-I/R小鼠，可不同程度地显著逆转irf8介导的中性粒细胞浸润和趋化因子释放增加。这项工作揭示了IRF8在肝脏微环境调节中的关键作用，并作为I/R损伤初始治疗的潜在靶点。
Hepatic ischemia/reperfusion (I/R) injury is an inevitable complication of hepatic surgery occasioned by liver transplantation and resection. The progression from liver ischemia to reperfusion injury is accompanied by abnormal metabolism, Kupffer cell activation, neutrophil recruitment and the release of cytokines. Activation of several interferon regulatory factors (IRFs) has been reported to either enhance or restrict I/R progression, but the role of IRF8 in the regulation of I/R injury progression is still unknown. In this study, we explore the IRF8 function in the I/R-mediated liver injury using overexpressed hepatic IRF8 and knockout mice. According to our results, IRF8 knockout mice had significantly lower inflammatory cells infiltration, inflammatory cytokines release and serum aspartate aminotransferase/alanine aminotransferase levels that improved the necrotic injury after I/R, unlike the control mice. Conversely, the overexpression of IRF8 in WT mice markedly aggravated the liver structure damage and its abnormal function. We further showed that IRF8-mediated inflammatory cells infiltration were partly dependent on early autophagy and NF-κΒ signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-κΒ signal pathway inhibitor secukinumab could drastically reverse the IRF8-mediated increase of neutrophil infiltration and chemokine release at different degrees. This work uncovered a critical role of IRF8 in the modulation of the hepatic microenvironment and as a potential target in the initial treatment of I/R injury.