Hypoxia-Inducible Factor-2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin-6

Authors

Rachel Y Gao
Meng Wang
Qihui Liu
Dechun Feng
Yankai Wen
Yang Xia
Sean P Colgan
Holger K Eltzschig
Cynthia Ju

Publication Date

6-1-2020

Journal

Hepatology

Abstract

BACKGROUND AND AIMS: 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, 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 targets for therapeutic interventions.

APPROACH AND RESULTS: We observed that APAP challenge caused stabilization of hypoxia-inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particularly HIF-2α. Genetic deletion of the HIF-2α gene in myeloid cells (HIF-2α

CONCLUSIONS: The data demonstrate that APAP treatment leads to HIF-2α stabilization in hepatic MΦs and that HIF-2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL-6, thereby ameliorating AILI.

Keywords

Acetaminophen, Analgesics, Non-Narcotic, Animals, Basic Helix-Loop-Helix Transcription Factors, Cellular Reprogramming, Chemical and Drug Induced Liver Injury, Gene Expression, Hypoxia, Immunity, Innate, Inactivation, Metabolic, Interleukin-6, Kupffer Cells, Mice, Mice, Knockout, Signal Transduction