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Loss of hypoxia inducible factor-1? aggravates ?? 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 ?? T cells during APAP-induced acute liver injury. In response to APAP administration, T-cell-specific Hif-1? 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-1? gene knockout mice. Loss of the Hif-1? gene enhanced the aberrant accumulation of IL-17A-producing innate-like ?? T cells in the affected liver with no apparent effects on their IL-17A-producing ability. Adoptive transfer of Hif-1?-deficient splenic ?? 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 ?? T cells. Furthermore, Hif-1?-deficient ?? 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-1? gene in T cells aggravates APAP-induced acute inflammatory responses by enhancing aberrant innate-like ?? T-cell recruitment, thereby increasing excessive neutrophil infiltration into the liver. (Hepatology Communications 2018;2:571-581).

SUBMITTER: Suzuki T

PROVIDER: S-EPMC5944581 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Suzuki Tomohiro T Minagawa Shoko S Yamazaki Takashi T Arai Takatomo T Kanai Mai M Shinjo Satoko S Goda Nobuhito N

Hepatology communications 20180326 5

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 ...[more]

PMID: 29761172

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Project description:Background & aimAcetaminophen (APAP)-induced acute liver failure is associated with substantial alterations in the hemostatic system. In mice, platelets accumulate in the liver after APAP overdose and appear to promote liver injury. Interestingly, patients with acute liver injury have highly elevated levels of the platelet-adhesive protein von Willebrand factor (VWF), but a mechanistic connection between VWF and progression of liver injury has not been established. We tested the hypothesis that VWF contributes directly to experimental APAP-induced acute liver injury.MethodsWild-type mice and VWF-deficient (Vwf-/-) mice were given a hepatotoxic dose of APAP (300 mg/kg, i.p.) or vehicle (saline). VWF plasma levels were measured by ELISA, and liver necrosis or hepatocyte proliferation was measured by immunohistochemistry. Platelet and VWF deposition were measured by immunofluorescence.ResultsIn wild-type mice, VWF plasma levels, high molecular weight (HMW) VWF multimers, and VWF activity decreased 24 h after APAP challenge. These changes coupled to robust hepatic VWF and platelet deposition, although VWF deficiency had minimal effect on peak hepatic platelet accumulation or liver injury. VWF plasma levels were elevated 48 h after APAP challenge, but with relative reductions in HMW multimers and VWF activity. Whereas hepatic platelet aggregates persisted in livers of APAP-challenged wild-type mice, platelets were nearly absent in Vwf-/- mice 48 h after APAP challenge. The absence of platelet aggregates was linked to dramatically accelerated repair of the injured liver. Complementing observations in Vwf-/- mice, blocking VWF or the platelet integrin αIIbβ3 during development of injury significantly reduced hepatic platelet aggregation and accelerated liver repair in APAP-challenged wild-type mice.ConclusionThese studies are the first to suggest a mechanistic link between VWF, hepatic platelet accumulation, and liver repair. Targeting VWF might provide a novel therapeutic approach to improve repair of the APAP-injured liver.Lay summaryPatients with acute liver injury due to acetaminophen overdose have highly elevated levels of the platelet-adhesive protein von Willebrand factor. It is not known whether von Willebrand factor plays a direct role in the progression of acute liver injury. We discovered that von Willebrand factor delays repair of the acetaminophen-injured liver in mice and that targeting von Willebrand factor, even in mice with established liver injury, accelerates liver repair.

Dataset Information

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

Publications

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

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