离体
炎症
酒精性肝炎
炎症体
医学
吡喃结构域
酒
肝损伤
免疫学
酒精性肝病
药理学
内科学
肝硬化
化学
生物化学
体外
作者
Marcelle Ribeiro,Arvin Iracheta-Vellve,Mrigya Babuta,Charles D. Calenda,Christopher Copeland,Yuan Zhuang,Patrick Lowe,Danielle Hawryluk,Donna Catalano,Yeonhee Cho,Bruce Barton,Srinivasan Dasarathy,Craig J. McClain,Arthur J. McCullough,Mack C. Mitchell,Laura E. Nagy,Svetlana Radaeva,Egil Lien,Douglas T. Golenbock,Gyongyi Szabo
出处
期刊:Hepatology
[Wiley]
日期:2023-03-03
卷期号:78 (1): 225-242
被引量:2
标识
DOI:10.1097/hep.0000000000000298
摘要
Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood.We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced-ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1β release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1β release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1β production, and steatohepatitis in a murine model of AH.Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.
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