Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.
At a glance
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This article reviews the early evolution of purine- release mechanisms, ATP-degrading enzymes and early purinergic receptors in bacteria, protozoa and algae.
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This article describes the trimeric structure of P2XRs and the parts involved in ATP binding, ion permeability and membrane trafficking.
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This report identifies ATP and UTP as 'find-me' signals released from pannexin 1 channels in apoptotic cells that attract phagocytes.
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This report shows that pannexin 1 is activated by caspase-mediated cleavage of its pore-associated C-terminal autoinhibitory region.
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This article shows that P2Y2R and A3R signalling controls purine gradient sensing and migration of neutrophils.
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This article shows that deletion of adenosine A2ARs enhances hepatic and systemic inflammatory responses.
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This paper shows that A2BRs are dually coupled to Gs and Gq-proteins and can elevate cAMP and Ca2+ levels.
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This paper shows that A2AR signalling inhibits TCR-induced activation of the PI3K–AKT pathway, thereby reducing IL-7Rα downregulation and naive T cell apoptosis.
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This paper shows that PKA inhibits signalling through the TCR by phosphorylating CSK.
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This report shows that immunosuppression by TReg cells is mediated in part by their expression of CD39 and CD73.
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This report shows that IL-6 increases ATP synthesis and release by TReg cells and stimulates their conversion to TH17 cells in vivo.
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This report shows that ADP-ribosylation activates rodent P2X7Rs and stimulates apoptosis of TReg cells and iNKT cells.
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- CD39/adenosine pathway is involved in AIDS progression. PLoS Pathog. 7, e1002110 (2011).
This report shows that HIV-1-positive patients have increased CD39 expression on TReg cells and that a CD39 gene polymorphism is associated with reduced CD39 expression and a slower progression to AIDS.
- Expression of ectonucleotidase CD39 by Foxp3+ TReg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007). et al.
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This paper demonstrates that deletion of CD39 elevates ATP levels in the inflamed liver and causes P2X7R-mediated apoptosis of iNKT cells.
- Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J. Exp. Med. 203, 2639–2648 (2006).
This paper shows that adenosine protects liver from ischaemia–reperfusion injury by activating A2ARs on iNKT cells.
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- Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. Blood 116, 5010–5020 (2010).
This study shows that activation of A2ARs inhibits activation of iNKT cells in mouse and human sickle cell disease.
- Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood 121, 3329–3334 (2013). et al.
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This study shows that ATP released from tumour cells in response to chemotherapy activates purinergic P2X7Rs on DCs and stimulates their secretion of IL-1β.
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This study shows that myeloid selective deletion of A2ARs slows tumour growth owing to indirect activation of T cells.
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- The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor α (IL-4Rα) signaling. Inflammation 36, 921–931 (2013). et al.
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- A feedback loop in PPARγ-adenosine A2A receptor signaling inhibits inflammation and attenuates lung damages in a mouse model of LPS-induced acute lung injury. Cell Signal. 25, 1913–1923 (2013). et al.
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- Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J. Clin. Invest. 122, 3931–3942 (2012).
This report shows that ex vivo A2AR-induced tolerization of DCs before adoptive cell transfer suppresses NKT cell activation and renal ischaemia–reperfusion injury.
- Adenosine A2A receptor, a potential valuable target for controlling reoxygenated DCs-triggered inflammation. Mol. Immunol. 63, 559–565 (2015). et al.
- Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101, 3985–3990 (2003). et al.
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This report shows that adenosine signalling through A2BRs stimulates DC polarization to tolerogenic, angiogenic and IL-6 producing cells.
- Modulation of murine dendritic cell function by adenine nucleotides and adenosine: involvement of the A2B receptor. Eur. J. Immunol. 38, 1610–1620 (2008). et al.
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This study shows that an interaction of ADA expressed on DCs with CD26 on human T cells enhances pro-inflammatory cytokine production.
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This study shows that inhibition of bladder tumour growth by theophylline, a non-selective adenosine receptor antagonist, is mediated primarily by A2BR, and not by A2AR, blockade.
- A3 and P2Y2 receptors control the recruitment of neutrophils to the lungs in a mouse model of sepsis. Shock 30, 173–177 (2008). , , , &
- An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models. BMC Infect. Dis. 8, 141 (2008). et al.
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- Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A2A receptor agonists. Br. J. Pharmacol. 132, 1017–1026 (2001). , , , &
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- Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model. Heart Rhythm. 11, 101–109 (2014).
This report shows that blockade of A2BR signalling beginning 1 week after myocardial infarction reduces heart failure.
- Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J. 24, 740–749 (2010). et al.
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This report shows that allosteric enhancement of A1R signalling increases myocardial IPC.
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- Evidence that the acute phase of ischemic preconditioning does not require signaling by the A 2B adenosine receptor. J. Mol. Cell. Cardiol. 49, 886–893 (2010). , , , &
- Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes. Circulation 111, 2190–2197 (2005). et al.
- Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114, 2056–2064 (2006). et al.
- The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors. Bas. Res. Cardiol. 110, 16 (2015). , , , &
- Improvement in microvascular reflow and reduction of infarct size with adenosine in patients undergoing primary coronary stenting. Am. J. Cardiol. 96, 1410–1415 (2005). et al.
- Autoimmunity in CD73/Ecto-5′-nucleotidase deficient mice induces renal injury. PloS ONE 7, e37100 (2012). et al.
- A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury. Am. J. Physiol. Renal Physiol. 303, F721–F732 (2012). et al.
- Kidney-specific reconstitution of the A1 adenosine receptor in A1 adenosine receptor knockout mice reduces renal ischemia-reperfusion injury. Kidney Int. 75, 809–823 (2009). et al.
- A1 adenosine receptor activation inhibits inflammation, necrosis, and apoptosis after renal ischemia-reperfusion injury in mice. J. Am. Soc. Nephrol. 15, 102–111 (2004). , , &
- Adenosine A2A receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation. Kidney Int. 80, 378–388 (2011). , , , &
- Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 290, F828–F837 (2006). et al.
- Selective A2A adenosine receptor activation reduces ischemia-reperfusion injury in rat kidney. Am. J. Physiol. 277, F404–F412 (1999). , , &
- Extracellular adenine nucleotides inhibit the activation of human CD4+ T lymphocytes. J. Immunol. 169, 15–21 (2002). et al.
- Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-α release. J. Immunol. 189, 4566–4573 (2012). et al.
- The reno-vascular A2B adenosine receptor protects the kidney from ischemia. PLoS Med. 5, e137 (2008). et al.
- Acute and delayed renal protection against renal ischemia and reperfusion injury with A1 adenosine receptors. Am. J. Physiol. Renal Physiol. 293, F1847–F1857 (2007). et al.
- The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L259–L271 (2012). , , , &
- Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg. 140, 440–446 (2010). et al.
- Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J. Immunol. 184, 5271–5279 (2010). et al.
- In vitro induction of T cells that are resistant to A2 adenosine receptor-mediated immunosuppression. Br. J. Pharmacol. 156, 297–306 (2009). et al.
- Adenosine A2A receptor activation on CD4+ T lymphocytes and neutrophils attenuates lung ischemia-reperfusion injury. J. Thorac. Cardiovascular Surg. 139, 474–482 (2010). et al.
- Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease. Am. J. Respiratory Cell. Mol. Biol. 49, 1038–1047 (2013). et al.
- A2B adenosine receptor expression by myeloid cells is proinflammatory in murine allergic-airway inflammation. J. Immunol. 189, 3707–3713 (2012). , , &
- Cross-talk between Gs- and Gq-coupled pathways in regulation of interleukin-4 by A2B adenosine receptors in human mast cells. Mol. Pharmacol. 70, 727–735 (2006). , , &
- Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. FASEB J. 29, 50–60 (2015).
This article shows that deletion of A2BRs from myeloid cells reduces pulmonary fibrosis.
- Blockade of IL-6 trans signaling attenuates pulmonary fibrosis. J. Immunol. 193, 3755–3768 (2014). et al.
- Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 62, 1665–1675 (2013). et al.
- Oxidized ATP inhibits T-cell-mediated autoimmunity. Eur. J. Immunol. 40, 2401–2408 (2010). et al.
- The development and immunosuppressive functions of CD4+CD25+FoxP3+ regulatory T cells are under influence of the adenosine- A2A adenosine receptor pathway. Frontiers Immunol. 3, 190 (2012). et al.
- Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G338–G346 (2014). et al.
- Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J. Immunol. 177, 2765–2769 (2006).
This article shows that deletion of A2ARs from TReg cells inhibits their ability to prevent colitis.
- Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129, 26–33 (2005). et al.
- Adenosine A2A receptor agonist-mediated increase in donor-derived regulatory T cells suppresses development of graft-versus-host disease. J. Immunol. 190, 458–468 (2013). et al.
- Adenosine 2A receptor is protective against renal injury in MRL/lpr mice. Lupus 20, 667–677 (2011). et al.
- CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 9325–9330 (2008).
This article shows that CD73 expression and A2AR signalling stimulate entry of lymphocytes into the CNS during EAE.
- Anti-inflammatory or proinflammatory effect of an adenosine receptor agonist on the Th17 autoimmune response is inflammatory environment-dependent. J. Immunol. 193, 5498–5505 (2014). et al.
- Roles of the adenosine receptor and CD73 in the regulatory effect of γδ T cells. PLoS ONE 9, e108932 (2014). et al.
- Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice. J. Immunol. 191, 4103–4111 (2013). &
- A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. J. Immunol. 188, 5713–5722 (2012). , , , &
- Blocking A2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation. J. Immunol. 190, 138–146 (2013). et al.
- Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl Acad. Sci. USA 110, 14711–14716 (2013).
This report shows that blockade of A2ARs prevents metastasis of tumours that express CD73.
- Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl Med. 7, 277ra230 (2015).
This report shows that respiratory hypoxia promotes the regression of spontaneous metastases from orthotopical breast tumours.
- Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652–3658 (2014). et al.
- A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput. Struct. Biotechnol. J. 13, 265–272 (2015).
This article reviews evidence that blockade of A2ARs enhances antitumour effects of checkpoint inhibitors, tumour vaccines and adoptive T cell transfer.
- Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547–1552 (2010).
This article shows that inhibition of CD73 inhibits growth and metastasis of orthotopic breast tumours.
- Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol. Immunother. 61, 917–926 (2012). et al.
- Adenosine receptor 2A blockade increases the efficacy of anti-pd-1 through enhanced antitumor t-cell responses. Cancer Immunol. Res. 3, 506–517 (2015). et al.
- Growth and metastasis of B16-F10 melanoma cells is not critically dependent on host CD73 expression in mice. BMC Cancer 14, 898 (2014). et al.
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This article shows that deletion of A2ARs results in the rejection of highly immunogenic melanoma and activates T cells.
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This report shows that T cell-specific deletion of A2ARs increases melanoma growth and reduces IL-7R expression in tumour-associated T cells.
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This report shows that activation of A2BRs on tumour cells promotes cell scattering and metastasis.
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This report shows that deletion of P2X7R reduces the immune response to tumours and enhances tumour growth.
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This study demonstrates species differences in mast cell responses to adenosine; degranulation is mediated by A3Rs in rodents and by A2BRs in primates and canines.
, , , &
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This study shows that degranulation of rat mast cells in mediated by A3R.
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This study shows that PDE4 inhibition and A2AR activation synergistically inhibit oxidative burst in human neutrophils.
, , &
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- Activation of the P2X7 receptor induces the rapid shedding of CD23 from human and murine B cells. Immunol. Cell Biol. 93, 77–85 (2015). , , &
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- Functional evidence for the expression of P2X1, 2X4 and P2X7 receptors in human lung mast cells. Br. J. Pharmacol. 157, 1215–1224 (2009). , , , &
- Expression of P2X5 in lymphoid malignancies results in LRH-1-specific cytotoxic T-cell-mediated lysis. Br. J. Haematol. 141, 799–807 (2008). et al.
- A truncation variant of the cation channel P2RX5 is upregulated during T cell activation. PloS ONE 9, e104692 (2014). , , &
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- Expression of P2X6 receptors in the enteric nervous system of the rat gastrointestinal tract. Histochem. Cell Biol. 133, 177–188 (2010). et al.
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- P2X7 receptor differentially couples to distinct release pathways for IL-1β in mouse macrophage. J. Immunol. 180, 7147–7157 (2008). , &
- TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J. Immunol. 190, 334–339 (2013). , &
- IL-1β production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J. 29, 4162–4173 (2015). et al.
- The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation. Thromb. Res. 111, 65–73 (2003). , , &
- P2Y4 receptor-mediated pinocytosis contributes to amyloid β-induced self-uptake by microglia. Mol. Cell. Biol. 33, 4282–4293 (2013). et al.
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- NAADP+ is an agonist of the human P2Y11 purinergic receptor. Cell Calcium 43, 344–355 (2008). et al.
- ADP acting on P2Y13 receptors is a negative feedback pathway for ATP release from human red blood cells. Circul. Res. 96, 189–196 (2005). et al.
- Purinergic P2X receptors: structural models and analysis of ligand-target interaction. Eur. J. Med. Chem. 89, 561–580 (2015). et al.