TY - JOUR
T1 - Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation
AU - De Carvalho Ribeiro, Marcelle
AU - Iracheta-Vellve, Arvin
AU - Babuta, Mrigya
AU - Calenda, Charles D.
AU - Copeland, Christopher
AU - Zhuang, Yuan
AU - Lowe, Patrick P.
AU - Hawryluk, Danielle
AU - Catalano, Donna
AU - Cho, Yeonhee
AU - Barton, Bruce
AU - Dasarathy, Srinivasan
AU - Mcclain, Craig
AU - Mccullough, Arthur J.
AU - Mitchell, Mack C.
AU - Nagy, Laura E.
AU - Radaeva, Svetlana
AU - Lien, Egil
AU - Golenbock, Douglas T.
AU - Szabo, Gyongyi
N1 - Publisher Copyright:
© 2023 John Wiley and Sons Inc.. All rights reserved.
PY - 2023/7
Y1 - 2023/7
N2 - 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, and steatohepatitis in a murine model of AH. Conclusions: 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.
AB - 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, and steatohepatitis in a murine model of AH. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85163498249&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85163498249&partnerID=8YFLogxK
U2 - 10.1097/HEP.0000000000000298
DO - 10.1097/HEP.0000000000000298
M3 - Article
C2 - 36862512
AN - SCOPUS:85163498249
SN - 0270-9139
VL - 78
SP - 225
EP - 242
JO - Hepatology
JF - Hepatology
IS - 1
ER -