Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury

Loi, Patrizia; Yuan, Qing; Torres, David; Delbauve, Sandrine; Laute, Marie-Aline; Lalmand, Marie-Claude; Pétein, Michel; Goriely, Stanislas; Goldman, Michel; Flamand, Véronique

doi:10.1002/hep.26022

Cited by 43 publications

(28 citation statements)

References 42 publications

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“…Most likely, IFN regulatory factor 3-dependent events control the IL-23/IL-17 axis in the liver, which is relevant to liver IRI (28). Our own data confirming expression of IL-1b and IL-23 in liver samples from IRI wt mice (data not shown) suggest these cytokines may play a role in driving T cells into IL-17A-releasing effector cells during IRI.…”

Section: Discussionmentioning

confidence: 51%

Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

Eggenhofer

Rovira

Sabet-Baktach

et al. 2013

The Journal of Immunology

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An emerging body of evidence suggests a pivotal role of CD3+ T cells in mediating early ischemia reperfusion injury (IRI). However, the precise phenotype of T cells involved and the mechanisms underlying such T cell–mediated immune responses in IRI, as well as their clinical relevance, are poorly understood. In this study, we investigated early immunological events in a model of partial warm hepatic IRI in genetically targeted mice to study the precise pathomechanistic role of RORγt+ T cells. We found that unconventional CD27−γδTCR+ and CD4−CD8− double-negative T cells are the major RORγt-expressing effector cells in hepatic IRI that play a mechanistic role by being the main source of IRI-mediating IL-17A. We further show that unconventional IRI-mediating T cells are contingent on RORγt, as highlighted by the fact that a genetic deficiency for RORγt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27−γδTCR+ and CD4−CD8− double-negative T cells as the major source of IL-17A via RORγt in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.

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Section: Discussionmentioning

confidence: 51%

Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

Eggenhofer

Rovira

Sabet-Baktach

et al. 2013

The Journal of Immunology

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“…In contrast, minor-to-no increases in IL-17A and IL-23 were measured during reperfusion in wild-type mice subjected to 60 min of 70% hepatic ischemia [8]. Only mice lacking the transcription factor interferon regulatory factor 3 exhibited an increase in IL-17A and IL-23 [8]. This last study therefore ruled out an involvement of IL-17A and IL-23 in hepatic I/R injury.…”

Section: Introductionmentioning

confidence: 76%

“…In addition, Tan et al [7] reported that RORγ + neutrophils drive hepatic I/R injury via an IL-1β/IL-23/IL-17A signaling axis, based on findings in a murine partial hepatic I/R model and plasma samples from 7 patients subjected to hepatic I/R. In contrast, minor-to-no increases in IL-17A and IL-23 were measured during reperfusion in wild-type mice subjected to 60 min of 70% hepatic ischemia [8]. Only mice lacking the transcription factor interferon regulatory factor 3 exhibited an increase in IL-17A and IL-23 [8].…”

Section: Introductionmentioning

confidence: 99%

IL-23 and IL-17 are not involved in hepatic ischemia reperfusion injury in mouse and man

2015

J Clin Transl Res

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Background: Hepatic ischemia and reperfusion (I/R) is common in liver surgery and transplantation and compromises postoperative liver function. Hepatic I/R injury is characterized by sterile inflammation that contributes to hepatocellular necrosis. Many immune cells and cytokines have been implicated in hepatic I/R injury. However, the role and relevance of IL-23 and IL-17A remains controversial in literature. Aim: To determine whether the IL-23/IL-17A signaling axis is activated in hepatic I/R using a triple-level experimental approach (in vitro, in vivo, and clinical). Methods: IL-23 and IL-17A were assayed by ELISA in the supernatant fractions of cultured murine (RAW 264.7) macrophages that were activated by supernatant fractions of necrotic cultured mouse (AML12) hepatocytes. Similarly, levels of these cytokines were determined in plasma samples and liver tissue of mice (N = 85) subjected to partial (70%) liver I/R. Finally, IL-23 and IL-17A were assayed in plasma samples obtained from a controlled cohort of liver resection patients who were either subjected to I/R (N = 27) or not (N = 13). Results: Activated macrophages did not produce IL-23 in response to supernatant of necrotic AML12 hepatocytes. IL-23 and IL-17A were not elevated in mice subjected hepatic I/R and were not elevated in serum from patients subjected to I/R during liver resection. Conclusion: IL-23 and IL-17A are not involved in hepatic I/R injury in mouse and man. Relevance for patients: If IL-23 and IL-17A were to mediate hepatocellular injury following I/R, these cytokines would constitute potential therapeutic targets. Since this study has revealed that IL-23 and IL-17A do not play a role in hepatic I/R, other pathways and therapeutic targets should be considered when developing modalities aimed at reducing hepatic I/R injury.

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“…6 Several reports have investigated the roles of IRF1 and IRF3 in liver IRI. 7,8 However, to the best of our knowledge, there are no data supporting the involvement of IRF5 during liver IRI. Therefore, this study was carried out to investigate the role of the TLR4/IRF5 signaling pathway in the hepatic IRI model, by evaluating mRNA expression levels of TLR4/IRF5 axis and its downstream genes, including tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β).…”

Section: Introductionmentioning

confidence: 90%

Evaluating mRNA Expression Levels of the TLR4/IRF5 Signaling Axis During Hepatic Ischemia-Reperfusion Injuries

Nasiri

Saadat²,

Karimi³

et al. 2017

Exp Clin Transplant

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Objectives: Hepatic ischemia and reperfusion during liver transplant surgery result in hepatocellular damage. Toll-like receptors, especially TLR4, have a fundamental basic role in the inflammatory phase of ischemia-reperfusion injuries. The effect of the TRIFdependent signaling pathway downstream of TLR4 in hepatic ischemia-reperfusion injury has been well established. However, the role of TLR4-MyD88-dependent signal transduction in hepatic ischemiareperfusion injury has not yet been clarified. The interferon regulatory factor 5 was introduced as the main regulator of the TLR4-MyD88 signaling pathway for activating proinflammatory cytokines. The present study was carried out to investigate the functional impact of the TLR4/IRF5 signaling axis in hepatic ischemia-reperfusion injury. Materials and Methods: mRNA expression levels of TLR4, IRF5, tumor necrosis factor α, interleukin 1β, and interleukin 6 were measured using real-time polymerase chain reaction after short (3 h) and long (168 h) reperfusion periods in a hepatic mouse model of ischemia-reperfusion injury in the presence and absence of N-acetylcysteine. Liver damage was evaluated by plasma levels of alanine aminotransferase and histopathology. Results: Our results show that mRNA levels of TLR4/IRF5 and its downstream cytokines were significantly elevated 3 hours after reperfusion and had drastically fallen to baseline levels 168 hours after reperfusion. Plasma levels of alanine aminotransferase showed the same pattern. Histopathologic study of the samples revealed significant hepatic cell infiltration and necrosis 168 hours after reperfusion. Pretreatment with N-acetylcysteine significantly decreased the mRNA levels of TLR4/IRF5 and its downstream cytokines 3 hours after reperfusion and subsequently improved the previously mentioned hepatic damages 168 hours after reperfusion. Conclusions: This study suggests a possible role for the TLR4/IRF5 signaling pathway in hepatic ischemiareperfusion injury. Furthermore, it reveals that Nacetylcysteine may suppress this inflammatory axis and consequently improve hepatic injuries.

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Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury

Cited by 43 publications

References 42 publications

Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

IL-23 and IL-17 are not involved in hepatic ischemia reperfusion injury in mouse and man

Evaluating mRNA Expression Levels of the TLR4/IRF5 Signaling Axis During Hepatic Ischemia-Reperfusion Injuries

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