Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation

Jay Luther, Sanjoy Khan, Manish K. Gala, Dmitry Kedrin, Gautham Sridharan, Russell P. Goodman, John J. Garber, Ricard Masia, Erik Diagacomo, Daniel Adams, Kevin R. King, Samuel Piaker, Hans Christian Reinecker, Martin L. Yarmush, Josepmaria Argemi, Ramon Bataller, Jules L. Dienstag, Raymond T. Chung, Suraj J. Patel

Research output: Contribution to journalArticle

Abstract

Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFNregulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcoholinjured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGASdriven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.

Original languageEnglish (US)
Article numberA65
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number21
DOIs
StatePublished - May 26 2020
Externally publishedYes

Keywords

  • Alcohol liver
  • CGAS
  • Connexin
  • IRF3
  • Innate immunity

ASJC Scopus subject areas

  • General

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  • Cite this

    Luther, J., Khan, S., Gala, M. K., Kedrin, D., Sridharan, G., Goodman, R. P., Garber, J. J., Masia, R., Diagacomo, E., Adams, D., King, K. R., Piaker, S., Reinecker, H. C., Yarmush, M. L., Argemi, J., Bataller, R., Dienstag, J. L., Chung, R. T., & Patel, S. J. (2020). Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation. Proceedings of the National Academy of Sciences of the United States of America, 117(21), [A65]. https://doi.org/10.1073/pnas.1911870117