Shen Y, Malik SA, Amir, M., Kumar, P., Cingolani, F., Wen, J., Liu, Y., Zhao, E., Farris, A. B., Raeman, R., & Czaja, M. J. Decreased Hepatocyte Autophagy Leads to Synergistic IL-1Î² and TNF Mouse Liver Injury and Inflammation [published online ahead of print, 2020 Feb 28]. Hepatology. 2020;10.1002/hep.31209. doi:10.1002/hep.31209.
Background & Aims
The proinflammatory cytokine IL€1Î² has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL€1Î² promotes liver injury in these diseases is unclear as no IL€1Î² receptor€linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy’s function in hepatotoxicity from proinflammatory cytokines.
Approach & Results
AML12 cells with decreased autophagy from a lentiviral Atg5 knockdown were resistant to toxicity from TNF, but sensitized to death from IL€1Î² which was markedly amplified by TNF co€treatment. IL€1Î²/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin€1s to prevent death. IL€1Î²/TNF depleted autophagy€deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL€1Î²/TNF€induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy€deficient cells. Mice with a tamoxifen€inducible, hepatocyte€specific Atg5 knockout were similarly sensitized to cathepsin dependent hepatocellular injury and death from IL€1Î²/TNF in combination, but neither IL€1Î² nor TNF alone. Knockout mice had increased hepatic inflammation, and IL€1Î²/TNF€treated, autophagy€deficient AML12 cells secreted exosomes with proinflammatory damage€associated molecular patterns (DAMPs).
The findings delineate novel mechanisms by which decreased hepatocyte autophagy promotes IL€1Î²/TNF€induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal DAMPs.
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