Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

Ledderose, Carola; Liu, Kaifeng; Kondo, Yutaka; Slubowski, Christian J.; Dertnig, Thomas; Denicoló, Sara; Arbab, Mona; Hübner, Johannes; Konrad, Kirstin; Fakhari, Mahtab; Lederer, James A.; Robson, Simon C.; Visner, Gary; Junger, Wolfgang G.

doi:10.1172/jci120972

Cited by 121 publications

(164 citation statements)

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“…Purinergic receptors are important in inflammation and immunity, and are expressed on immune cells including antigen‐presenting cells and T cells . In general, the activation of P2 receptors by extracellular ATP exerts proinflammatory effects, including T‐cell activation and migration . In contrast, hydrolysis of ATP to adenosine by a pathway involving ecto‐nucleoside triphosphate diphosphohydrolase‐1 (CD39) and ecto‐5′‐nucleotidase (CD73) commonly results in anti‐inflammatory effects via activation of ARs …”

Section: Introductionmentioning

confidence: 99%

“…6 In general, the activation of P2 receptors by extracellular ATP exerts proinflammatory effects, 7 including T-cell activation and migration. 8,9 In contrast, hydrolysis of ATP to adenosine by a pathway involving ecto-nucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5 0 -nucleotidase (CD73) commonly results in anti-inflammatory effects via activation of ARs. 10 ATP, released from activated, damaged or dying cells, can activate P2 receptors and promote inflammatory responses in transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

2019

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Allogeneic hematopoietic stem cell transplantation is a curative therapy for a number of hematological malignancies, but is limited by the development of graft‐versus‐host disease (GVHD). CD39 and CD73 form an ectoenzymatic pathway that hydrolyzes extracellular adenosine 5′‐triphosphate (ATP) to adenosine, which respectively exacerbate or alleviate disease in allogeneic mouse models of GVHD. The current study aimed to explore the role of the CD39/CD73 pathway and adenosine receptor (AR) blockade in a humanized mouse model of GVHD. Immunodeficient nonobese diabetic‐severe combined immunodeficiency‐IL‐2 receptor γnull mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist αβ‐methylene‐ADP (APCP) (50 mg kg−1) or saline for 7 days, or the AR antagonist caffeine (10 mg kg−1) or saline for 14 days. Mice predominantly engrafted human CD4+ and CD8+ T cells, with smaller proportions of human regulatory T cells, invariant natural killer T cells, monocytes and dendritic cells. Neither APCP nor caffeine altered engraftment of these human leukocyte subsets. APCP (CD39/CD73 blockade) augmented GVHD as shown through increased weight loss and worsened liver histology, including increased leukocyte and human T‐cell infiltration, and increased apoptosis. This treatment also increased serum human IL‐2 concentrations and decreased the frequency of human CD39− CD73− CD4+ T cells. In contrast, caffeine (AR blockade) did not alter GVHD severity or human serum cytokine concentrations (IL‐2, IL‐6, IL‐10 or tumor necrosis factor‐α). In conclusion, blockade of CD39/CD73 but not ARs augments disease in a humanized mouse model of GVHD. These results indicate that CD39/CD73 blockade maintains sufficient extracellular ATP concentrations to promote GVHD in this model.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

2019

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“…Immune cells including macrophages infiltrate grafts and contribute to chronic rejection, and pharmacologic inhibition of P2X7 receptor signaling has been shown to inhibit macrophage infiltration and prevent vascular damage in a model of heart allograft transplantation . In addition, Vergani et al demonstrated that P2X7 receptor expression is upregulated in graft‐infiltrating lymphocytes in cardiac‐transplanted humans and mice and that P2X7 receptor antagonism resulted in improved long‐term cardiac transplant survival, while direct production of ATP and subsequent activation of the P2X4 receptor has been shown to regulate T cell migration (recent advances in specific roles of ATP in lymphocyte activation and rejection are reviewed by Castillo‐Leon and colleagues). In the setting of cardiac transplantation, D’Addio et al showed that the P2X7 receptor/NLR Family Pyrin Domain Containing 3 (NLRP3) complex maintains a physiological NLRP3‐mediated Th2 program, while intracellular mutation of P2X7 receptor induces NLRP3 displacement in T cells, causing Th17 skewing and subsequent poor allograft outcome.…”

Section: Atp and Adenosine In Graft Rejection And Resolution Of Inflamentioning

confidence: 99%

Extracellular nucleotide signaling in solid organ transplantation

Yeudall

Leitinger

Laubach

2020

American Journal of Transplantation

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The role of extracellular purine nucleotides, including adenosine triphosphate (ATP) and adenosine, as modulators of posttransplantation outcome and ischemia‐reperfusion injury is becoming increasingly evident. Upon pathological release of ATP, binding and activation of P2 purinergic surface receptors promote tissue injury and inflammation, while the expression and activation of P1 receptors for adenosine have been shown to attenuate inflammation and limit ischemia‐induced damage, which are central to the viability and long‐term success of allografts. Here we review the current state of the transplant field with respect to the role of extracellular nucleotide signaling, with a focus on the sources and functions of extracellular ATP. The connection between ischemia reperfusion, purinergic signaling, and graft preservation, as well as the role of ATP and adenosine as driving factors in the promotion and suppression of posttransplant inflammation and allograft rejection, are discussed. We also examine novel therapeutic approaches that take advantage of the ischemia‐reperfusion‐responsive and immunomodulatory roles for purinergic signaling with the goal of enhancing graft viability, attenuating posttransplant inflammation, and minimizing complications including rejection, graft failure, and associated comorbidities.

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“…Macrophage activation is critically modulated by extracellular ATP and associated purinergic signaling via autocrine/paracrine mechanisms (6). During sepsis, purinergic signaling regulates core inflammatory cell functions such as migration and inflammatory mediators production (6)(7)(8). ATP depletion or blockade of purinergic receptors were shown to increase survival and improve outcome of sepsis in rodent models (9,10).…”

Section: Sepsis Is Associated With High Mortality and Was Now Recognimentioning

confidence: 99%

Connexin-43 dependent ATP release mediates macrophage activation during peritonitis

Dosch¹,

Zindel²,

Jebbawi³

et al. 2018

Preprint

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Brief Summary:Connexin-43-mediated ATP release from macrophages in response to agonists modulates autocrine activation of macrophages in a P2Y1-dependent manner, ultimately determining sepsis survival. 3 ABSTRACT Peritonitis is the consequence of bacterial spillage into a sterile environment by gastrointestinal hollow-organ perforation that may lead to fulminant sepsis. Outcome of peritonitis-induced sepsis critically depends on macrophage activation by extracellular ATP release and associated para-and autocrine signaling via purinergic receptors. Mechanisms that mediate and control ATP release, however, are poorly understood. Here we show that TLR-2 and -4 agonists trigger ATP release via Connexin-43 (CX43) hemichannels in peritoneal macrophages leading to poor survival during sepsis. In humans, CX43 expression was upregulated on macrophages isolated from the peritoneal cavity in patients with intraperitoneal infection but not in healthy controls. Using a murine caecal ligation and puncture (CLP) model, we identified increased CX43 expression in activated infiltrating peritoneal, hepatic and pulmonary macrophages. Conditional MAC-CX43 KO Lyz2 cre/cre Cx43 flox/flox mice were developed to specifically assess the CX43 impact in macrophages. Both macrophagespecific CX43 deletion (using Lyz2 cre/cre Cx43 flox/flox mice) or pharmacological CX43 blockade were associated with reduced cytokine secretion by macrophages in response to LPS and CLP. This was ultimately resulting in increased survival in Lyz2 cre/cre Cx43 flox/flox mice and after pharmacological blockade. Specific inhibition of the purinergic receptor P2RY1 abrogated CX43 elicited cytokine responses. In conclusion, inhibition of autocrine ATP signaling via CX43 on macrophages and P2RY1 improves sepsis outcome in experimental peritonitis.

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Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

Cited by 121 publications

References 58 publications

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

Extracellular nucleotide signaling in solid organ transplantation

Connexin-43 dependent ATP release mediates macrophage activation during peritonitis

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