期刊
BIOCHEMICAL PHARMACOLOGY
卷 192, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114728
关键词
Hepatic ischemia; reperfusion; Interferon regulatory factor 8; Autophagy; Inflammatory response; Neutrophils
资金
- National Natural Science Foundation of China [82003788, 81903656, 81673468, 81672752]
- Natural Science Foundation of Jiangsu Province [BK20180560, BK20190801, BK20180575]
- China Postdoctoral Science Foundation [2018 M632430]
- Double First-Class University project [CPU2018GF10, CPU2018GY46]
- Youth Project of Natural Science Foundation of Nanjing University of Chinese Medi-cine [NZY82003788]
- Scientific Startup Foundation for High level Scientists of China Pharmaceutical University [3154070026]
The study revealed the critical role of IRF8 in modulating hepatic microenvironment and its potential as a target for early treatment of I/R injury. Knockout of IRF8 reduced inflammatory cell infiltration, cytokine release, and liver enzyme levels after I/R, while overexpression aggravated liver damage. Additionally, IRF8-mediated inflammatory cell infiltration was partly dependent on autophagy and NF-kappa B signal pathway during I/R.
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-kappa B signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-kappa B 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据