Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury

Ko, Gang Jee; Jang, Hye Ryoun; Huang, Yanfei; Womer, Karl L.; Liu, Manchang; Higbee, Elizabeth; Xiao, Zuoxiang; Yagita, Hideo; Racusen, Lorraine C.; Hamad, Abdel Rahim A.; Rabb, Hamid

doi:10.1681/asn.2010010121

Cited by 41 publications

(41 citation statements)

References 42 publications

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“…TNF receptor 1/2 double-deficient mice are not protected from renal IRI, and interference with TNF does not protect mice from IRI (45). However, other members of the TNF superfamily have recently been implicated in the induction of necroptosis [e.g., TNF related apoptosis inducing ligand receptor (TRAIL-R) (46), Fas, or TWEAK] and are just as likely to be involved as members of the Toll-like receptors, some of which may trigger the intracellular RHIM-containing protein TRIF (TIR-domain-containing adapter-inducing interferon-β) (16).…”

Section: Discussionmentioning

confidence: 98%

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Linkermann

Bräsen

Darding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

505

456

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Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptorinteracting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.RIP3 | RIP1 | programmed necrosis | apoptosis

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Section: Discussionmentioning

confidence: 98%

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Linkermann

Bräsen

Darding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

505

456

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“…These low numbers could reflect low sensitivity of this assay by flow cytometry, or this finding may suggest that although circulatory TNF-a plays a predominant role in mediating TNFR-dependent pulmonary apoptosis, T cell-dependent apoptosis occurs through an alternative death receptor pathway. For example, Fas ligand has been identified as a key mediator of renal injury, and FasL-deficient mice exhibited fewer infiltrating TNF-aproducing T lymphocytes in the kidney and renal lymph nodes (31). Alternatively, TNFR1 may be selectively upregulated in pulmonary ECs independent of T cell TNFR1 expression.…”

Section: Discussionmentioning

confidence: 99%

Lung T Lymphocyte Trafficking and Activation during Ischemic Acute Kidney Injury

Lie

White

Santora

et al. 2012

The Journal of Immunology

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Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia–reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3+ T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3+CD8+ phenotype; however, both CD3+CD4+ and CD3+CD8+ T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (Tnu/nu) mice. Adoptive transfer of murine wild-type T lymphocytes into Tnu/nu mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney–lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.

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“…22 It was reported that blockade of the Fas/FasL interaction attenuated IRI both in the kidney 23 and in the liver. 24 So we isolated thymocytes, liver mononuclear cells (MNCs) and splenocytes, which were subjected to flow cytometry analyses.…”

Section: Hif-2a Knockout Led To Upregulated Fasl Expression On Periphmentioning

confidence: 99%

“…FasL blockade was implemented by in vivo administration of a functional-grade purified anti-mouse FasL antibody, as previously described. 23 Anti-FasL Ab (16-5911; eBioscience) or control hamster IgG (control Ab) were injected intraperitoneally (500 mg per mouse) at 24 hours before IR insult, and a booster injection at half dose was administered immediately after the initiation of reperfusion.…”

Section: Nk11 + Cell Depletion and Fasl Blockadementioning

confidence: 99%

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Zhang

Han

Dai

et al. 2016

Journal of the American Society of Nephrology

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Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2a in T/NKT cells and found that HIF-2a knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2a knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1 + cell depletion or Fas ligand blockade.Compared with wild-type NKT cells, HIF-2a 2/2 NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. Mechanistically, hypoxia-induced expression of adenosine A2A receptor in NKT cells and CGS21680-induced cAMP production in thymocytes were HIF-2a-dependent. Hydrogen peroxide-induced Fas ligand expression on thymic wild-type NKT cells was significantly attenuated by CGS21680 treatment, but this effect was lost in HIF-2a 2/2 NKT cells. Finally, CGS21680 and LPS, an inducer of HIF-2a in endothelium, synergistically reduced renal IRI substantially, but this effect was absent in Mx1-Cre-induced global HIF-2a-knockout mice. Taken together, our results reveal a hypoxia/HIF-2a/adenosine A2A receptor axis that restricts NKT cell activation when confronted with oxidative stress and thus protects against renal IRI.

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Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury

Cited by 41 publications

References 42 publications

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Lung T Lymphocyte Trafficking and Activation during Ischemic Acute Kidney Injury

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

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