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

Abstract

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)

Regulatory mechanism of HIF-1α and its role in liver diseases: a narrative review

“…A previous study also demonstrated accumulation of neutrophils in the liver of HIF-1α-deficient mice and a decrease in plasma concentrations of IL-6 and regulated on activation, normal T cell expressed and secreted (RANTES), indicating a change in the inflammatory response (108). Suzuki et al (109) also found that HIF-1α gene deletion in T cells aggravates the acute inflammatory response induced by APAP. The underlying mechanism involves abnormal recruitment of natural-like γδT cells, increasing excessive neutrophil infiltration in the liver.…”

Hypoxia signaling in human diseases and therapeutic targets

“…HIF1A is also stabilized in the liver with severe APAP injury, which stimulates the cleavage of hemojuvelin, a cofactor of bone morphogenic protein, thereby downregulating the expression of hepcidin 62 . T-cell-specific deletion of HIF1A worsens APAP-induced acute liver injury by increasing hepatic accumulation of innate-like γδ T-cells and neutrophils 63 . HIF has also been shown to be beneficial during hepatic IRI injury.…”

Hypoxia and HIF Signaling: One Axis with Divergent Effects

“…The protective role of HIF1-α has been demonstrated recently in murine models of acute hepatic inflammation. T-cells-specific deletion of HIF1-α increases neutrophil infiltration and the recruitment of aberrant γδ T-cells into the liver, finally favoring acute hepatic inflammation [ 115 ]. Genetic deletion of the HIF2-α gene in myeloid cells reduces the progression of acute liver disease by inducing liver macrophages to overexpress IL-6 and protects against acute injury [ 116 ].…”