Hypoxia-Inducible Factor (HIF)-2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury via the Production of Interleukin-6.

Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one-third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine (NAC), declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover novel targets for therapeutic interventions. We observed that APAP challenge caused the stabilization of hypoxia-inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particular HIF-2α. Genetic deletion of the HIF-2α gene in myeloid cells (HIF-2α ^mye/- ) markedly exacerbated APAP-induced liver injury (AILI) without affecting APAP bio-activation and detoxification. In contrast, hepatic and serum levels of the hepato-protective cytokine interleukin (IL)-6, its downstream signal transducer and transcription factor 3 (STAT3) activation in hepatocytes, as well hepatic MΦs IL-6 expression were markedly reduced in HIF-2α ^mye/- mice compared to WT mice post APAP challenge. In vitro experiments revealed that hypoxia induced IL-6 production in hepatic MΦs and that such induction was abolished in HIF-2α-deleted hepatic MΦs. Restoration of IL-6 by administration of exogenous IL-6 ameliorated AILI in HIF-2α ^mye/- mice. Finally, IL-6-mediated hepatoprotection against AILI was abolished in hepatocyte-specific IL-6 receptor knockout mice. CONCLUSION: the data demonstrate that APAP treatment leads to HIF-2α stabilization in hepatic MΦs and HIF-2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL-6, thereby ameliorating AILI.