Distinct contributions of CD4<sup>+</sup>T cell subsets in hepatic ischemia/reperfusion injury

Kuboki, Satoshi; Sakai, Nozomu; Tschöp, Johannes; Edwards, Michael J.; Lentsch, Alex B.; Caldwell, Charles C.

doi:10.1152/ajpgi.90464.2008

Cited by 67 publications

(77 citation statements)

References 42 publications

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“…14 Adoptive transfer studies showed that CD73 KO Tregs, which cannot convert adenosine monophosphate to adenosine, are unable to protect WT mice from kidney IRI. 37 47,54 having no effect in other studies, 48,51,52 and protecting from injury in one ischemic stroke study. 46 The reasons for conflicting results between studies in the same organ may be technical differences in the injury models (e.g., severity of injury in control mice) or methods of Treg depletion (e.g., PC61 versus diphtheria toxin-mediated depletion of FoxP3 + Tregs).…”

Section: Role Of Adenosine In Treg-mediated Kidney Protectionmentioning

confidence: 86%

Regulatory T Cells in AKI

Kinsey

Sharma

Okusa

2013

Journal of the American Society of Nephrology

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Human AKI is manifested by inflammation, and an early feature in the pathogenesis is the accumulation of immune cells in the kidney. To understand the pathophysiology of AKI, results from animal models have shown a causal relation between the leukocyte activation and infiltration to the kidney after kidney ischemia-reperfusion. Blocking the activation or trafficking of proinflammatory leukocytes into the kidney preserves renal function and histologic integrity. In contrast, the anti-inflammatory lymphocytes called regulatory T cells have an intrinsic renal-protective function and may represent a novel therapeutic approach and/or target for pharmacological manipulation to ameliorate AKI. This review will highlight the recent insight gained into the role and mechanisms of regulatory T cells in AKI.

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Section: Role Of Adenosine In Treg-mediated Kidney Protectionmentioning

confidence: 86%

Regulatory T Cells in AKI

Kinsey

Sharma

Okusa

2013

Journal of the American Society of Nephrology

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“…Using warm and cold hepatic I/R models, studies have shown different roles for liver-resident versus blood-borne DCs, highlighting the importance of the local microenvironment in determining DC function during hepatic IRI [6-8]. Additionally, a previous study determined that CD4+ T cells play an important role in liver IRI [9]. Activated CD4+ T cells exhibit various immune functions with distinctive phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Zheng¹,

Li²,

Wei³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The present study aimed to evaluate the effects as well as the underlying mechanisms of bone marrow-derived dendritic cells (BMDCs) and exosomes produced by BMDCs (DEXs) on hepatic ischemia-reperfusion (I/R) injury (IRI). Methods: Primary hepatocytes were isolated and used to mimic the liver IR microenvironment. BMDCs were induced and characterized both biochemically with a flow cytometer (FCM) and biophysically with a microscope. Then, we exposed BMDCs to the supernatants from primary hepatocytes and evaluated the maturation of BMDCs by FCM. BMDCs were systemically injected into mice before liver IR via the tail vein, and the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), inflammatory cytokines, and histological changes were respectively examined by ELISA, RT-qPCR and microscopy. Furthermore, we isolated DEXs by ultracentrifugation, characterized DEXs by transmission electron microscopy (TEM) and nanosight tracking analysis (NTA) and western blotting (WB), and then we co-cultured BMDCs/DEXs and naïve T cells and performed FCM, ELISA and confocal imaging. Moreover, we injected DEXs into mice prior to liver IR via the tail vein and examined its therapeutic effects by microscopy and ELISA. Finally, inhibitors of HSP70 (cmHSP70.1), PI3K (BKM120) and mTOR (Rapamycin) were used to investigate the role of HSP70 and the PI3K/mTOR axis in the effects of DEXs on naïve T cells by WB and FCM. Results: Bone marrow cells were efficiently induced into dendritic cells (DCs) with typical DC characteristics. The supernatants from primary hepatocytes exposed to H/R upregulated DC maturation markers. After DC administration, liver IR injury was improved with histopathological scores and serum transaminases. Additionally, we found that the anti-inflammatory cytokines TGF-β, Foxp3 and interleukin (IL)-10 were upregulated and that IL-17 was downregulated. Furthermore, confocal imaging revealed that the uptake of H/R-DEXs by naïve T cells was greater than that of DEXs derived from the control or negative group of BMDCs, and this increase was correlated with a significantly greater degree of differentiation of Tregs and Th17 cells. Moreover, H/R-DEXs administration improved liver function in mice after IR. Finally, the inhibition of HSP70, PI3K and mTOR completely abolished the effect of DEXs on naïve T cells. Conclusion: These results demonstrated that BMDCs and DEXs could alleviate hepatic I/R injury via modulating the balance between Tregs and Th17 cells. DEXs transported HSP70 into naïve T cells and stimulated the PI3K/mTOR axis to modulate the balance between Tregs and Th17 cells and protect the liver from IR injury.

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“…At the same time, Kupffer cells and hepatocytes also generate ROS, leading to direct damage of endothelial cells and hepatocytes. Due to their important role, ROS levels are tightly regulated through different pathways 33. The major regulators are ROS scavengers that include SOD, catalase, and glutathione peroxidase (GSH-Px).…”

Section: Discussionmentioning

confidence: 99%

Some mechanisms of the protective effect of ischemic preconditioning on rat liver ischemia-reperfusion injury

Adam¹

2014

IJGM

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Ischemia-reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cascade of deleterious cellular responses, leading to inflammation, cell death, and ultimate organ failure. Increasing experimental evidence has suggested that Kupffer cells and T-cells mediate activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase system is among the most critical of the cytoprotective mechanisms activated during cellular stress, exerting antioxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. Finally, the activation of toll-like receptors on Kupffer cells may play a fundamental role in exploring new therapeutic strategies based on the concept that hepatic I/R injury represents a case for host “innate” immunity. In the present study, there was a significant decrease in hepatic activity of glycogen in the I/R group as compared with corresponding values in the control group. On the other hand, there was a significant increase in the hepatic activity of glycogen in the I/R-IP (ischemic preconditioning) group as compared with corresponding values in the I/R group.

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Distinct contributions of CD4⁺T cell subsets in hepatic ischemia/reperfusion injury

Abstract: Kuboki S, Sakai N, Tschöp J, Edwards MJ, Lentsch AB, Caldwell CC. Distinct contributions of CD4 ϩ T cell subsets in hepatic ischemia/reperfusion injury.

Cited by 67 publications

References 42 publications

Regulatory T Cells in AKI

Regulatory T Cells in AKI

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Some mechanisms of the protective effect of ischemic preconditioning on rat liver ischemia-reperfusion injury

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Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

Abstract: Kuboki S, Sakai N, Tschöp J, Edwards MJ, Lentsch AB, Caldwell CC. Distinct contributions of CD4 ϩ T cell subsets in hepatic ischemia/reperfusion injury.

Cited by 67 publications

References 42 publications

Regulatory T Cells in AKI

Regulatory T Cells in AKI

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Some mechanisms of the protective effect of ischemic preconditioning on rat liver ischemia-reperfusion injury

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Distinct contributions of CD4⁺T cell subsets in hepatic ischemia/reperfusion injury