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

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 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 () and . Neutrophil depletion and IL-17A neutralization completely abolished the aggravated phenotypes in T-cell-specific gene knockout mice. Loss of the 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 -deficient splenic γδ T cells into recombination activating gene 2 ()-deficient mice aggravated APAP-induced liver injury with increased neutrophil accumulation in the liver compared to that of wild-type γδ T cells. Furthermore, -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. Deletion of 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. ( 2018;2:571-581).