Extracellular histones stimulate collagen expression in vitro and promote liver fibrogenesis in a mouse model via the TLR4-MyD88 signaling pathway  

作　　者：Zhi Wang Zhen-Xing Cheng Simon T Abrams Zi-Qi Lin ED Yates Qian Yu Wei-Ping Yu Ping-Sheng Chen Cheng-Hock Toh Guo-Zheng Wang 

机构地区：[1]Department of Pathology and Pathophysiology,Medical School,Southeast University,Nanjing 210009,Jiangsu Province,China [2]Department of Gastroenterology,Zhongda Hospital,Nanjing 210009,Jiangsu Province,China [3]Department of Clinical Infection,Microbiology and Immunology,University of Liverpool,Liverpool L697BE,United Kingdom [4]Department of Integrated Traditional Chinese and Western Medicine,Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre,West China Hospital,Sichuan University,Chengdu 610041,Sichuan Province,China [5]Department of Integrative Biology,University of Liverpool,Liverpool L697ZB,United Kingdom [6]Roald Dahl Haemostasis&Thrombosis Ctr,Royal Liverpool University Hospital,Liverpool L697BE,United Kingdom

出　　处：《World Journal of Gastroenterology》2020年第47期7513-7527,共15页世界胃肠病学杂志（英文版）

基　　金：Supported by Key R&D Program of Jiangsu Province,No.BE2019712;British Heart Foundation,No.PG/14/19/30751 and No.PG/16/65/32313.

摘　　要：BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood.Recently,the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis.Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated.AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis.METHODS In vitro,LX2 human hepatic stellate cells(HSCs)were treated with histones in the presence or absence of non-anticoagulant heparin(NAHP)for neutralizing histones or TLR4-blocking antibody.The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining.In vivo,the CCl4-induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice.Circulating histones were detected and the effect of NAHP was evaluated.RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I.Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody.In CCl4-treated wild type mice,circulating histones were dramatically increased and maintained high levels during the duration of fibrosisinduction.Injection of NAHP not only reduced alanine aminotransferase and liver injury scores,but also significantly reduced fibrogenesis.Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC,the CCl4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl4-induced liver fibrosis.The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice.CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones.

关 键 词：Liver fibrosis Extracellular histones Non-anticoagulant heparin TLR4 MYD88 CCL4 

分 类 号：R575.2[医药卫生—消化系统]