IRF-1 Promotes Liver Transplant Ischemia/Reperfusion Injury via Hepatocyte IL-15/IL-15Rα Production

Yokota, Shinichiro; Yoshida, Osamu; Dou, Liping; Spadaro, Angela; Isse, Kumiko; Ross, Mark A.; Stolz, Donna B.; Kimura, Shoko; Du, Qiang; Demetris, Anthony J.; Thomson, Angus W.; Geller, David A.

doi:10.4049/jimmunol.1402505

Cited by 43 publications

(33 citation statements)

References 73 publications

(123 reference statements)

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“…Tumor suppressor gene p53-mediated cell arrest, as well as ROS and ER stress has been implicated in IFN-γ-induced hepatocyte apoptosis 59 . Additionally, IRF-1 was shown to regulate expressions and secretions of IL-15 and IL-15Rα in hepatocytes to facilitate infiltration and activation of NK, NKT, and CD8(+) T cells in livers 60 , which constitutes potentially an indirect cytotoxic mechanism.…”

Section: Innate Immune Effector Mechanismsmentioning

confidence: 99%

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

et al. 2016

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Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory, but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver IRI involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver IRI in patients.

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Section: Innate Immune Effector Mechanismsmentioning

confidence: 99%

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

et al. 2016

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“…Hepatocytes constitute 80% of the cells in the liver and express IL-15 and IL-15Rα [20,27]. To determine whether the NK cell homeostasis is maintained by IL-15 from hepatocytes or macrophages, we analysed the intra-hepatic lymphocyte populations following deletion of IL-15Rα in hepatocytes or macrophages by crossing Il15ra fl/fl mice with mice expressing the Cre-recombinase either in liver under the albumin promoter ( Alb-Cre ) or in macrophages under the lysozyme promoter (( LysM-Cre ).…”

Section: Resultsmentioning

confidence: 99%

“…Liver resident macrophages called Kupffer cells are one of the major subsets that express IL-15 [10,18]. IL-15 from stellate cells has been shown to support the homeostasis of NKT cells [19], while hepatocytes are a significant source of IL-15:IL-15Rα complex [20]. Thus any of the above mentioned populations could support the survival of IL-15 dependent T cell subsets in the liver.…”

Section: Introductionmentioning

confidence: 99%

Homeostasis of IL-15 dependent lymphocyte subsets in the liver

et al. 2016

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IL-15 is a member of the gamma chain family of cytokines (γc – CD132). The IL-15 receptor (IL-15R) complex consists of 3 subunits: the ligand-binding IL-15Rα chain (CD215), the β chain (CD122; also used by IL-2), and the common γ chain. The biological activities of IL-15 are mostly mediated by the IL-15:IL-15Rα complex, produced by the same cell and ‘trans-presented’ to responder cells expressing the IL-15Rβγc. The peculiar and almost unique requirement for IL-15 to be trans-presented by IL-15Rα suggests that the biological effects of IL-15 signaling are tightly regulated even at the level of availability of IL-15. Tissue-specific deletion of IL-15Rα has shown macrophage-and dendritic cell-derived IL-15Rα mediate the homeostasis of different CD8+ T cell subsets. Here we show that hepatocyte and macrophage- specific expression of IL-15Rα is required to maintain the homeostasis of NK and NKT cells in the liver. Thus, homeostasis of IL-15-dependent lymphocyte subsets is also regulated by trans-presentation of IL-15 by non-hematopoietic cells in the tissue environment.

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“…Interferon regulatory factor 1 fosters I/R injury via hepatocyte IL-15/IL-15Rα production [28] . In contrast, CD39 expression on conventional liver myeloid DC limits their proinflammatory activity and confers protective properties on these important innate immune cells against liver transplant I/R injury [29] .…”

Section: Discussionmentioning

confidence: 99%

Depletion of CD11c<sup>+</sup> Cells Does Not Influence Outcomes in Mice Subjected to Transient Middle Cerebral Artery Occlusion

Kraft

Scholtyschik²,

Schuhmann³

et al. 2017

Neuroimmunomodulation

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Objective: While it has been shown that different T-cell subsets have a detrimental role in the acute phase of ischemic stroke, data on the impact of dendritic cells (DC) are missing. Classic DC can be characterized by the cluster of differentiation (CD)11c surface antigen. Methods: In this study, we depleted CD11c⁺ cells by using a CD11c-diphtheria toxin (DTX) receptor mouse strain that allows selective depletion of CD11c⁺ cells by DTX injection. For stroke induction, we used the model of transient middle cerebral artery occlusion (tMCAO) and analyzed stroke volume and functional outcome on days 1 and 3 as well as expression of prototypical pro- and anti-inflammatory cytokines on day 1 after tMCAO. Three different protocols for CD11c⁺ cell depletion, tMCAO duration, and readout time point were applied. Results: Injection of DTX (5 or 100 ng/g) reliably depleted CD11c⁺ cells without influencing the fractions of other immune cell subsets. CD11c⁺ cell depletion had no impact on stroke volume, but mice with a longer DTX pretreatment performed worse than those with vehicle treatment. CD11c⁺ cell depletion led to a decrease in cortical interleukin (IL)-1β and IL-6 messenger ribonucleic acid levels. Conclusions: We show, for the first time, that CD11c⁺ cell depletion does not influence stroke volume in a mouse model of focal cerebral ischemia. Nevertheless, given the unspecificity of the CD11c surface antigen for DC, mouse models that allow a more selective depletion of DC are needed to investigate the role of DC in stroke pathophysiology.

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IRF-1 Promotes Liver Transplant Ischemia/Reperfusion Injury via Hepatocyte IL-15/IL-15Rα Production

Cited by 43 publications

References 73 publications

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

Homeostasis of IL-15 dependent lymphocyte subsets in the liver

Depletion of CD11c<sup>+</sup> Cells Does Not Influence Outcomes in Mice Subjected to Transient Middle Cerebral Artery Occlusion

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