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Acetaminophen (APAP)‐induced liver injury is closely associated with acute hepatic inflammation. Hypoxia‐inducible factor‐1 (HIF‐1) is activated during immunological processes and regulates gene expressions in various types of immune cells. Although HIF‐1 controls the differentiation and functions of conventional T cells in chronic inflammation, the pathological importance of HIF‐1 in innate‐like T cells during acute inflammation remains unknown. Here, we investigated the role of HIF‐1 in innate‐like γδ T cells during APAP‐induced acute liver injury. In response to APAP administration, T‐cell‐specific  Hif‐1α  gene knockout mice sustained severe liver damage compared to wild‐type control mice but without any impacts on the initial hepatic insult. This severe liver damage was accompanied by excessive neutrophil infiltration into the liver, increased serum interleukin (IL)‐17A levels, and increased hepatic expressions of C‐X‐C chemokine ligand ( Cxcl )  1  and  Cxcl2 . Neutrophil depletion and IL‐17A neutralization completely abolished the aggravated phenotypes in T‐cell‐specific  Hif‐1α  gene knockout mice. Loss of the  Hif‐1α  gene enhanced the aberrant accumulation of IL‐17A‐producing innate‐like γδ T cells in the affected liver with no apparent effects on their IL‐17A‐producing ability. Adoptive transfer of  Hif‐1α ‐deficient splenic γδ T cells into recombination activating gene 2 ( Rag2 )‐deficient mice aggravated APAP‐induced liver injury with increased neutrophil accumulation in the liver compared to that of wild‐type γδ T cells. Furthermore,  Hif‐1α ‐deficient γδ T cells selectively showed aberrantly enhanced migratory ability. This ability was totally abolished by treatment with the mitochondrial adenosine triphosphate synthase inhibitor oligomycin.  Conclusion:  Deletion of  Hif‐1α  gene in T cells aggravates APAP‐induced acute inflammatory responses by enhancing aberrant innate‐like γδ T‐cell recruitment, thereby increasing excessive neutrophil infiltration into the liver. ( Hepatology Communications  2018;2:571‐581)

Loss of hypoxia inducible factor‐1α aggravates γδ T‐cell‐mediated inflammation during acetaminophen‐induced liver injury