Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation

作者：Marcelle de Carvalho 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, Gyöngyi Szabó · 发表于：Hepatology · 年份：2023 · DOI：10.1097/hep.0000000000000298 · 被引用次数：18 · 研究领域：Alcohol Consumption and Health Effects、Alcoholism and Thiamine Deficiency、Vagus Nerve Stimulation Research

BACKGROUND AIMS: 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. APPROACH RESULTS: 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...