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IL‐17a exacerbates hepatic ischemia–reperfusion injury in fatty liver by promoting neutrophil infiltration and mitochondria‐driven apoptosis
Author(s) -
Yang Xinxiang,
Li Changxian,
Ng Kevin TakPan,
Liu Jiang,
Liu Hui,
Zhang Weiyi,
Xiao Fan,
Li Xiangcheng,
Lo Chung Mau,
Lu Liwei,
Man Kwan
Publication year - 2020
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3ma0520-716r
Subject(s) - fatty liver , biology , liver injury , reperfusion injury , steatohepatitis , liver function , infiltration (hvac) , steatosis , apoptosis , ischemia , endocrinology , medicine , immunology , pathology , biochemistry , physics , disease , thermodynamics
Hepatic ischemia–reperfusion (IR) injury is a critical issue during liver transplantation (LT). Recent studies have demonstrated that IL‐17a contributes to IR injury and steatohepatitis. However, the underlying mechanism is not understood. This study aimed to examine the role of IL‐17a on hepatic IR injury in fatty liver and to investigate the underlying mechanisms. The correlation between serum IL‐17a levels and liver function was analyzed in LT patients receiving fatty ( n = 42) and normal grafts ( n = 44). Rat LT model was applied to validate the clinical findings. IL‐17a knockout (KO) and wild‐type mice were fed with high‐fat diets to induce fatty liver and subjected to hepatic IR injury with major hepatectomy. Frequency of circulating neutrophils and IL‐17a expression on PBMCs were analyzed by flow cytometry. Mitochondrial outer membrane permeabilization (MOMP) was examined by a living intravital image system. Serum IL‐17a was elevated after human LT, especially with fatty grafts. The aspartate aminotransferase and alanine transaminase levels were increased in recipients with fatty grafts compared with normal grafts. In rat LT model, the intragraft IL‐17a expression was significantly higher in fatty grafts than normal ones post‐LT. KO of IL‐17a in mice notably attenuated liver damage after IR injury in fatty liver, characterized by better‐preserved liver architecture, improved liver function, and reduced neutrophil infiltration. MOMP triggered cell death after hepatic IR injury in a caspase‐independent way via IL‐17a/NF‐κB signaling pathway. KO of IL‐17a protected the fatty liver against IR injury through the suppression of neutrophil infiltration and mitochondria‐driven apoptosis.