Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

Eggenhofer, Elke; Rovira, Jordi; Sabet-Baktach, M.; Groell, Anja; Scherer, Marcus N.; Dahlke, Marc-Hendrik; Farkas, S.; Loss, Martin; Koehl, Gudrun E.; Lang, Sven A.; Melter, Michael; Schlitt, Hans J.; Geissler, Edward K.; Kroemer, Alexander

doi:10.4049/jimmunol.1202975

Cited by 28 publications

(26 citation statements)

References 29 publications

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“…All animals were euthanized 24 h following transient ischaemia/reperfusion. The surgical procedure was performed as described elsewhere 44 . In brief, C57BL/6J mice were narcotized with xylazine/ketamine and shaved at their front.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

et al. 2014

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Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4−/− mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4−/− mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.

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Section: Methodsmentioning

confidence: 99%

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

et al. 2014

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“…Th17 cells contribute to the inflammatory response by mediating the recruitment of macrophages and neutrophils to injured tissues 7 . Moreover, RORγt-expressing (RORγt + ) T cells are the main source of Th17-producing cells during the early phase of liver IRI 8 . We previously demonstrated that RORγt/IL-17A + -expressing T cells played a crucial role in mediating hepatic IRI 9 .…”

Section: Introductionmentioning

confidence: 99%

Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1α signaling pathway in liver inflammatory injury

et al. 2018

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Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays important roles in regulating immune and metabolic homeostasis. Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) transcription factors are crucial for the regulation of immune cell function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1α activity, leading to Foxp3 downregulation and RORγt and IL-17A upregulation in IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1α and upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. Silencing of HIF-1α in ATF3 KO mice ameliorated IRI-induced liver damage in parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1α signaling, which was crucial for the modulation of TLR4-driven inflammatory responses and T cell development. The present study provides potential therapeutic targets for the treatment of liver IRI followed by liver transplantation.

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“…hepatocytes by DN T cells. CD3+ DN T cells also have been shown to play a role in amplifying early ischemia reperfusion injury (Eggenhofer et al , 2013). The ability of DN T cells to respond to ischemic or APAP induced liver injury and amplify the course of hepatotoxicity that evolves over the first 3–24 hours suggests that these T cells have insufficient time to develop adaptive immune responses to non-self antigens and thus are more likely to be responding via innate immune response mechanisms or TCR responses to auto- or neo-antigens exposed or produced as part of hepatocyte injury.…”

Section: Discussionmentioning

confidence: 99%

The role of intrahepatic CD3+/CD4−/CD8− double negative T (DN T) cells in enhanced acetaminophen toxicity

Getachew

Cusimano

James

et al. 2014

Toxicology and Applied Pharmacology

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The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB −/−) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB −/−) mice. Analysis revealed that GrB −/− mice had an increased population of intrahepatic CD3 (+), CD4 (−), CD8 (−) lymphocytes expressing the CD69 activation marker and Fas Ligand. Depletion of these cells in the GrB −/− and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB −/− IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. Conclusions Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (−), CD8 (−), NK1.1 (−) T cells. Depletion of these cells from GrB −/− mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery.

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Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

Cited by 28 publications

References 29 publications

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1α signaling pathway in liver inflammatory injury

The role of intrahepatic CD3+/CD4−/CD8− double negative T (DN T) cells in enhanced acetaminophen toxicity

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