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Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation.
de Carvalho Ribeiro, Marcelle; Iracheta-Vellve, Arvin; Babuta, Mrigya; Calenda, Charles D; Copeland, Christopher; Zhuang, Yuan; Lowe, Patrick P; Hawryluk, Danielle; Catalano, Donna; Cho, Yeonhee; Barton, Bruce; Dasarathy, Srinivasan; McClain, Craig; McCullough, Arthur J; Mitchell, Mack C; Nagy, Laura E; Radaeva, Svetlana; Lien, Egil; Golenbock, Douglas T; Szabo, Gyongyi.
Afiliación
  • de Carvalho Ribeiro M; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Iracheta-Vellve A; Monte Rosa Therapeutics, Boston, Massachusetts, 02210, USA.
  • Babuta M; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
  • Calenda CD; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Copeland C; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Zhuang Y; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Lowe PP; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Hawryluk D; Brigham and Women's General Hospital, Boston, Massachusetts, USA.
  • Catalano D; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Cho Y; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
  • Barton B; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Dasarathy S; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
  • McClain C; Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
  • McCullough AJ; Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA.
  • Mitchell MC; Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA.
  • Nagy LE; Division of Gastroenterology, University of Louisville, Louisville, Kentucky, USA.
  • Radaeva S; Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA.
  • Lien E; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • Golenbock DT; Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA.
  • Szabo G; Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA.
Hepatology ; 78(1): 225-242, 2023 07 01.
Article en En | MEDLINE | ID: mdl-36862512
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-1ß 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-1ß 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-1ß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hepatitis / Hepatitis Alcohólica Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Hepatology Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hepatitis / Hepatitis Alcohólica Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Hepatology Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos