Neutrophil extracellular traps promote acetaminophen-induced acute liver injury in mice via AIM2  

作　　者：Fan-le Zeng Yuan Zhang Zhong-hao Wang Hui Zhang Xue-teng Meng Yi-qin Wu Zhen-zhen Qian Yu-hao Ding Jun Li Tao-tao Ma Cheng Huang 

机构地区：[1]Inflammation and Immune Mediated Diseases Laboratory of Anhui Province,Anhui Institute of Innovative Drugs,School of Pharmacy,Anhui Medical University,Hefei,230032,China [2]Anhui Provincial Institute of Translational Medicine,Hefei,230032,China

出　　处：《Acta Pharmacologica Sinica》2024年第8期1660-1672,共13页中国药理学报（英文版）

基　　金：supported by funding from National Natural Science Foundation of China(U19A2001);Anhui Fund for Distinguished Young Scholars(2022AH020050);the Scientific Research Promoti on Fund of Anhui Medical University(2022xkjT010);Scientific Reasearch Platform Improvement Project of Anhui Medical University(2023xkjT049);Research Fund of Anhui Institute of translational medicine(2021zhyx-B06,2022zhyx-B07).

摘　　要：Excessive acetaminophen(APAP)can induce neutrophil activation and hepatocyte death.Along with hepatocyte dysfunction and death,NETosis(a form of neutrophil-associated inflammation)plays a vital role in the progression of acute liver injury(ALI)induced by APAP overdose.It has been shown that activated neutrophils tend to migrate towards the site of injury and participate in inflammatory processes via formation of neutrophil extracellular traps(NETs).In this study we investigated whether NETs were involved in hepatocyte injury and contributed to APAP-induced ALI progression.ALI mouse model was established by injecting overdose(350 mg/kg)of APAP.After 24 h,blood and livers were harvested for analyses.We showed that excessive APAP induced multiple programmed cell deaths of hepatocytes including pyroptosis,apoptosis and necroptosis,accompanied by significantly increased NETs markers(MPO,citH3)in the liver tissue and serum.Preinjection of DNase1(10 U,i.p.)for two consecutive days significantly inhibited NETs formation,reduced PANoptosis and consequently alleviated excessive APAP-induced ALI.In order to clarify the communication between hepatocytes and neutrophils,we induced NETs formation in isolated neutrophils,and treated HepaRG cells with NETs.We found that NETs treatment markedly increased the activation of GSDMD,caspase-3 and MLKL,while pre-treatment with DNase1 down-regulated the expression of these proteins.Knockdown of AIM2(a cytosolic innate immune receptor)abolished NETs-induced PANoptosis in HepaRG cells.Furthermore,excessive APAP-associated ALI was significantly attenuated in AIM2KO mice,and PANoptosis occurred less frequently.Upon restoring AIM2 expression in AIM2KO mice using AAV9 virus,both hepatic injury and PANoptosis was aggravated.In addition,we demonstrated that excessive APAP stimulated mtROS production and mitochondrial DNA(mtDNA)leakage,and mtDNA activated the TLR9 pathway to promote NETs formation.Our results uncover a novel mechanism of NETs and PANoptosis in APAP-associated ALI,which might ser

关 键 词：acute liver injury APAP PANoptosis NETS AIM2 TLR9 

分 类 号：R575[医药卫生—消化系统]