Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

Li, Li; Huang, Liping; Ye, Hong; Song, Steven; Bajwa, Amandeep; Lee, Sang Ju; Moser, Emily K.; Jaworska, Katarzyna; Kinsey, Gilbert R.; Day, Yuan Ji; Linden, Joel; Lobo, Peter I.; Rosin, Diane L.; Okusa, Mark D.

doi:10.1172/jci63170

Cited by 140 publications

(126 citation statements)

References 71 publications

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“…Upon tissue injury, the release of Hmgb1, along with other DAMPs, guides neutrophils and monocytes to sites of sterile inflammation. Neutrophils and monocytes in turn release a vast arsenal of hydrolytic, oxidative, and pore-forming molecules with the potential to cause profound collateral tissue destruction (28); such destruction signals for further recruitment of neutrophils and monocytes, eliciting even A B more tissue damage in a vicious cycle that is ultimately regulated by both pro-and antiinflammatory signals (29,30). Histological assessment of livers after I/R shows lobular and portal inflammation in both WT and Aag −/− samples (Fig.…”

Section: Significancementioning

confidence: 99%

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Ebrahimkhani

Daneshmand

Mazumder

et al. 2014

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

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Inflammation is accompanied by the release of highly reactive oxygen and nitrogen species (RONS) that damage DNA, among other cellular molecules. Base excision repair (BER) is initiated by DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the alkyladenine DNA glycosylase (Aag/Mpg) excises several DNA base lesions induced by the inflammation-associated RONS release that accompanies ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag −/− mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag −/− mice display decreased hepatocyte death, cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic DNA strand breaks that trigger poly (ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and necrosis; indeed, steady-state levels of abasic sites and nuclear PAR polymers were significantly more elevated in wild-type vs. Aag −/− liver after I/R. This increase in PAR polymers was accompanied by depletion of intracellular NAD and ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (Hmgb1) nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile inflammation, and present a novel target for controlling I/R-induced injury.DNA repair | base excision | Aag/Mpg DNA glycosylase | ischemia reperfusion | liver

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Section: Significancementioning

confidence: 99%

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Ebrahimkhani

Daneshmand

Mazumder

et al. 2014

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

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“…Compared with mature DCs, immature DCs interact actively with T cells and direct them into a regulatory response. In kidney IRI, BMDCs tolerized with an A 2A R agonist 22 or DCs deficient of S1pr3 10 attenuate AKI. Most of the biologic effects of S1P are mediated through the S1PR family, which includes the ubiquitously expressed S1P1, S1P2 , and S1P3 subtypes.…”

Section: /2mentioning

confidence: 99%

“…DCs are heterogeneous, professional antigen-presenting immune cells, and they are distributed throughout the lymphoid and nonlymphoid tissues. 21 Previously, we found that adoptive transfer of bone marrow-derived dendritic cells (BMDCs) 22 or T regulatory cells (T REG s) pretreated with an A 2A receptor agonist 23 significantly reduced renal IRI. In regards to S1PR expression, human and mouse leukocytes express similar levels of S1PRs.…”

mentioning

confidence: 99%

Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

Bajwa

Huang

Kurmaeva

et al. 2016

Journal of the American Society of Nephrology

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The plasticity of dendritic cells (DCs) permits phenotypic modulation ex vivo by gene expression or pharmacologic agents, and these modified DCs can exert therapeutic immunosuppressive effects in vivo through direct interactions with T cells, either inducing T regulatory cells (T REG s) or causing anergy. Sphingosine 1-phosphate (S1P) is a sphingolipid and the natural ligand for five G protein-coupled receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), and S1PR agonists reduce kidney ischemia-reperfusion injury (IRI) in mice. S1pr3 2/2 mice are protected from kidney IRI, because DCs do not mature. We tested the therapeutic advantage of S1pr3 2/2 bone marrow-derived dendritic cell (BMDC) transfers in kidney IRI. IRI produced a rise in plasma creatinine (PCr) levels in mice receiving no cells (NCs) and mice pretreated with wild-type (WT) BMDCs. However, S1pr3 2/2 BMDC-pretreated mice were protected from kidney IRI. S1pr3 2/2BMDC-pretreated mice had significantly higher numbers of splenic T REG s compared with NC and WT BMDC-pretreated mice. S1pr3 2/2 BMDCs did not attenuate IRI in splenectomized, Rag-1 2/2 , or CD11c + DC-depleted mice. Additionally, S1pr3 2/2 BMDC-dependent protection required CD169 + marginal zone macrophages and the macrophage-derived chemokine CCL22 to increase splenic CD4 + Foxp3 + T REG s.Pretreatment with S1pr3 2/2 BMDCs also induced T REG -dependent protection against IRI in an allogeneic mouse model. In summary, adoptively transferred S1pr3 2/2 BMDCs prevent kidney IRI through interactions within the spleen and expansion of splenic CD4 + Foxp3 + T REG s. We conclude that genetically induced deficiency of S1pr3 in allogenic BMDCs could serve as a therapeutic approach to prevent IRI-induced AKI.

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“…A 2B receptor activation protects against acute kidney injury via inhibition of neutrophil-dependent release of tumour necrosis factor-α [116]. Dendritic cells activated by A 2A receptor agonists attenuate acute renal injury [221]. A review describing adenosine generation and signalling during acute kidney injury is available [20].…”

Section: Renal Injury and Failurementioning

confidence: 99%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

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Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

Cited by 140 publications

References 71 publications

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

Purinergic signalling in the kidney in health and disease

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