Sex-Specific Regulation of Interferon-γ Cytotoxicity in Mouse Liver by Autophagy.

Yang Shen, Francesca Cingolani, Shoaib Ahmad Malik, Jing Wen, Yunshan Liu, Mark J Czaja

Hepatology (Baltimore, Md.) 2021 Nov

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Interferon-γ (IFNγ) is a central activator of immune responses in the liver and other organs. IFNγ triggers tissue injury and inflammation in immune diseases, which occur predominantly in females for unknown reasons. Recent findings that autophagy regulates hepatotoxicity from proinflammatory cytokines led to an examination of whether defective hepatocyte autophagy underlies sex-specific liver injury and inflammation induced by IFNγ. A lentiviral autophagy-related 5 (Atg5) knockdown was performed to decrease autophagy-sensitized alpha mouse liver (AML 12) hepatocytes to death from IFNγ in combination with IL-1β or TNF. Death was necrosis attributable to impaired energy homeostasis and adenosine triphosphate depletion. Male mice with decreased autophagy from a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were resistant to IFNγ hepatotoxicity whereas female knockout mice developed liver injury and inflammation. Female mice had increased IFNγ-induced signal transducer and activator of transcription 1 (STAT1) levels compared to males. Blocking STAT1, but not interferon regulatory factor 1, signaling prevented IFNγ-induced hepatocyte death in autophagy-deficient AML12 cells and female mice. The mechanism of death is STAT1-induced overexpression of nitric oxide synthase 2 (NOS2) as in vitro hepatocyte death and in vivo liver injury were blocked by NOS2 inhibition. Decreased hepatocyte autophagy sensitizes mice to IFNγ-induced liver injury and inflammation through overactivation of STAT1 signaling that causes NOS2 overexpression. Hepatotoxicity is restricted to female mice, suggesting that sex-specific effects of defective autophagy may underlie the increased susceptibility of females to IFNγ-mediated immune diseases. © 2021 by the American Association for the Study of Liver Diseases.

Citation

Yang Shen, Francesca Cingolani, Shoaib Ahmad Malik, Jing Wen, Yunshan Liu, Mark J Czaja. Sex-Specific Regulation of Interferon-γ Cytotoxicity in Mouse Liver by Autophagy. Hepatology (Baltimore, Md.). 2021 Nov;74(5):2745-2758