Decreased Macrophage Autophagy Promotes Liver Injury and Inflammation from Alcohol

Ghulam Ilyas, Francesca Cingolani, Enpeng Zhao, Kathryn E. Tanaka, Mark J. Czaja

Research output: Contribution to journalArticle

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Abstract

Background: One mechanism underlying the development of alcoholic liver disease is overactivation of the innate immune response. Recent investigations indicate that the lysosomal pathway of autophagy down-regulates the inflammatory state of hepatic macrophages, suggesting that macrophage autophagy may regulate innate immunity in alcoholic liver disease. The function of macrophage autophagy in the development of alcoholic liver disease was examined in studies employing mice with a myeloid-specific decrease in autophagy. Methods: Littermate control and Atg5 Δmye mice lacking Atg5-dependent myeloid autophagy were administered a Lieber–DeCarli control (CD) or ethanol diet (ED) alone or together with lipopolysaccharide (LPS) and examined for the degree of liver injury and inflammation. Results: Knockout mice with decreased macrophage autophagy had equivalent steatosis but increased mortality and liver injury from ED alone. Increased liver injury and hepatocyte death also occurred in Atg5 Δmye mice administered ED and LPS in association with systemic inflammation as indicated by elevated serum levels of proinflammatory cytokines. Hepatic macrophage and neutrophil infiltration were unaffected by decreased autophagy, but levels of proinflammatory cytokine gene induction were significantly increased in the livers but not adipose tissue of knockout mice treated with ED and LPS. Inflammasome activation was increased in ED/LPS-treated knockout mice resulting in elevated interleukin (IL)-1β production. Increased IL-1β promoted alcoholic liver disease as liver injury was decreased by the administration of an IL-1 receptor antagonist. Conclusions: Macrophage autophagy functions to prevent liver injury from alcohol. This protection is mediated in part by down-regulation of inflammasome-dependent and inflammasome-independent hepatic inflammation. Therapies to increase autophagy may be effective in this disease through anti-inflammatory effects on macrophages.

Original languageEnglish (US)
JournalAlcoholism: Clinical and Experimental Research
DOIs
StatePublished - Jan 1 2019

Fingerprint

Macrophages
Autophagy
Liver
Alcohols
Inflammation
Alcoholic Liver Diseases
Wounds and Injuries
Nutrition
Inflammasomes
Ethanol
Lipopolysaccharides
Diet
Knockout Mice
Interleukin-1
Innate Immunity
Down-Regulation
Cytokines
Interleukin-1 Receptors
Neutrophil Infiltration
Infiltration

Keywords

  • Alcoholic Liver Disease
  • Inflammasome
  • Interleukin-1β
  • Lipopolysaccharide
  • Tumor Necrosis Factor

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Decreased Macrophage Autophagy Promotes Liver Injury and Inflammation from Alcohol. / Ilyas, Ghulam; Cingolani, Francesca; Zhao, Enpeng; Tanaka, Kathryn E.; Czaja, Mark J.

In: Alcoholism: Clinical and Experimental Research, 01.01.2019.

Research output: Contribution to journalArticle

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N2 - Background: One mechanism underlying the development of alcoholic liver disease is overactivation of the innate immune response. Recent investigations indicate that the lysosomal pathway of autophagy down-regulates the inflammatory state of hepatic macrophages, suggesting that macrophage autophagy may regulate innate immunity in alcoholic liver disease. The function of macrophage autophagy in the development of alcoholic liver disease was examined in studies employing mice with a myeloid-specific decrease in autophagy. Methods: Littermate control and Atg5 Δmye mice lacking Atg5-dependent myeloid autophagy were administered a Lieber–DeCarli control (CD) or ethanol diet (ED) alone or together with lipopolysaccharide (LPS) and examined for the degree of liver injury and inflammation. Results: Knockout mice with decreased macrophage autophagy had equivalent steatosis but increased mortality and liver injury from ED alone. Increased liver injury and hepatocyte death also occurred in Atg5 Δmye mice administered ED and LPS in association with systemic inflammation as indicated by elevated serum levels of proinflammatory cytokines. Hepatic macrophage and neutrophil infiltration were unaffected by decreased autophagy, but levels of proinflammatory cytokine gene induction were significantly increased in the livers but not adipose tissue of knockout mice treated with ED and LPS. Inflammasome activation was increased in ED/LPS-treated knockout mice resulting in elevated interleukin (IL)-1β production. Increased IL-1β promoted alcoholic liver disease as liver injury was decreased by the administration of an IL-1 receptor antagonist. Conclusions: Macrophage autophagy functions to prevent liver injury from alcohol. This protection is mediated in part by down-regulation of inflammasome-dependent and inflammasome-independent hepatic inflammation. Therapies to increase autophagy may be effective in this disease through anti-inflammatory effects on macrophages.

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