Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells

Day, Yuan-Ji; Huang, Liping; McDuffie, Marcia; Rosin, Diane L.; Ye, Hong; Chen, Jiang‐Fan; Schwarzschild, Michael A.; Fink, Jeffrey; Linden, Joel; Okusa, Mark D.

doi:10.1172/jci200315483

Cited by 83 publications

(113 citation statements)

References 27 publications

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“…Chemokines mediate leukocyte migration into the injured kidney and IFN-␥ modulates chemokine production, including IFN-␥-inducing protein 10 (IP-10), monokine-induced by IFN-␥, and IFN-␥-inducible T cell chemoattractant production, which bind to CXCR3 to mediate T cell migration (25) (25)(26)(27)(28)(29)(30). Our previous study showed that renal IRI up-regulated IP-10 and MIP␣, MIP1␤, MIP2, which are thought to mediate T cell and neutrophil migration (31,32). The source of increased IFN-␥ production upon stimulation by IL-12 is mainly from Th1, NKT (14,33,34), and myeloid cells (35).…”

Section: Discussionmentioning

confidence: 98%

NKT Cell Activation Mediates Neutrophil IFN-γ Production and Renal Ischemia-Reperfusion Injury

Li¹,

Huang²,

Sung³

et al. 2007

The Journal of Immunology

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296

352

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Previous work has shown that ischemia-reperfusion (IR) injury (IRI) is dependent on CD4+ T cells from naive mice acting within 24 h. We hypothesize that NKT cells are key participants in the early innate response in IRI. Kidneys from C57BL/6 mice were subjected to IRI (0.5, 1, 3, and 24 h of reperfusion). After 30 min of reperfusion, we observed a significant increase in CD4+ cells (145% of control) from single-cell kidney suspensions as measured by flow cytometry. A significant fraction of CD4+ T cells expressed the activation marker, CD69+, and adhesion molecule, LFA-1high. Three hours after reperfusion, kidney IFN-γ-producing cells were comprised largely of GR-1+CD11b+ neutrophils, but also contained CD1d-restricted NKT cells. Kidney IRI in mice administered Abs to block CD1d, or deplete NKT cells or in mice deficient of NKT cells (Jα18−/−), was markedly attenuated. These effects were associated with a significant decrease in renal infiltration and, in activation of NKT cells, and a decrease in IFN-γ-producing neutrophils. The results support the essential role of NKT cells and neutrophils in the innate immune response of renal IRI by mediating neutrophil infiltration and production of IFN-γ.

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Section: Discussionmentioning

confidence: 98%

NKT Cell Activation Mediates Neutrophil IFN-γ Production and Renal Ischemia-Reperfusion Injury

Li¹,

Huang²,

Sung³

et al. 2007

The Journal of Immunology

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296

352

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“…33,34 Although adora2a is located in the kidney, 35,36 the protection afforded by adora2a agonists is an effect on T/NKT cells in ischemic renal injury. 6,8,37 So far, several studies have suggested an important link between HIFs and adenosinerelated molecules. For example, HIF-1 regulates A2B adenosine receptor expression.…”

Section: Discussionmentioning

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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“…In fact, adenosine is a potent anti-inflammatory agent with A 2A Rs triggering BOFF^signals in activated immune cells, which constitutes one of the most fundamental and immediate tissue-protecting mechanisms (reviewed in [295,296]). A 2A R agonists were even named Bthe most potent anti-inflammatory drug known to mankind.^Ac-cordingly, activation of A 2A Rs has been shown to confer a robust protection against tissue damage from ischemiaYreperfusion injury in different organ such as heart [297Y299], blood vessels [300], kidney [301,302], liver [303,304], lung [305,306], joints [307], skin [308,309], and even in the spinal cord [310,311] and in the brain following hemorrhage [312] or acute infection [313]. Thus, it is the activation (rather the blockade) of A 2A Rs that confers protection against damage triggered by inflammation in peripheral tissues, precisely the opposite of what is observed in the damaged adult brain.…”

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

470

428

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells

Cited by 83 publications

References 27 publications

NKT Cell Activation Mediates Neutrophil IFN-γ Production and Renal Ischemia-Reperfusion Injury

NKT Cell Activation Mediates Neutrophil IFN-γ Production and Renal Ischemia-Reperfusion Injury

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

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

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