Adenosine is Required for Sustained Inflammasome Activation Via the A₂A Receptor and the HIF-1α Pathway

Overview

Journal Nat Commun

Specialty Biology

Date 2013 Dec 20

PMID 24352507

Citations 57

Authors

Xinshou Ouyang

Ayaz Ghani

Ahsan Malik

Tuere Wilder

Oscar Rene Colegio

Richard Anthony Flavell

Bruce Neil Cronstein

Wajahat Zafar Mehal

Affiliations

Soon will be listed here.

Abstract

Inflammasome pathways are important in chronic diseases; however, it is not known how the signalling is sustained after initiation. Inflammasome activation is dependent on stimuli such as lipopolysaccharide (LPS) and ATP that provide two distinct signals resulting in rapid production of interleukin (IL)-1β, with the lack of response to repeat stimulation. Here we report that adenosine is a key regulator of inflammasome activity, increasing the duration of the inflammatory response via the A(2A) receptor. Adenosine does not replace signals provided by stimuli such as LPS or ATP but sustains inflammasome activity via a cAMP/PKA/CREB/HIF-1α pathway. In the setting of the lack of IL-1β responses after previous exposure to LPS, adenosine can supersede this tolerogenic state and drive IL-1β production. These data reveal that inflammasome activity is sustained, after initial activation, by A(2A) receptor-mediated signalling.

Citing Articles

The Essential Role of Angiogenesis in Adenosine 2A Receptor Deficiency-mediated Impairment of Wound Healing Involving c-Ski via the ERK/CREB Pathways.

Peng Y, Xiong R, Wang B, Chen X, Ning Y, Zhao Y Int J Biol Sci. 2024; 20(11):4532-4550.

PMID: 39247808 PMC: 11380447. DOI: 10.7150/ijbs.98856.

Lipotoxicity and immunometabolism in ischemic acute kidney injury: current perspectives and future directions.

Otunla A, Shanmugarajah K, Davies A, Shalhoub J Front Pharmacol. 2024; 15:1355674.

PMID: 38464721 PMC: 10924325. DOI: 10.3389/fphar.2024.1355674.

Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice.

Yang Q, Cai Y, Ma Q, Xiong A, Xu P, Zhang Z Sci Transl Med. 2024; 16(737):eadk3868.

PMID: 38446902 PMC: 11373239. DOI: 10.1126/scitranslmed.adk3868.

NLRP3 and cancer: Pathogenesis and therapeutic opportunities.

Tengesdal I, Dinarello C, Marchetti C Pharmacol Ther. 2023; 251:108545.

PMID: 37866732 PMC: 10710902. DOI: 10.1016/j.pharmthera.2023.108545.

Inhibition of the interaction between microglial adenosine 2A receptor and NLRP3 inflammasome attenuates neuroinflammation posttraumatic brain injury.

Du H, Li C, Gao R, Tan Y, Wang B, Peng Y CNS Neurosci Ther. 2023; 30(1):e14408.

PMID: 37564004 PMC: 10805470. DOI: 10.1111/cns.14408.

References

Sohail M, Hashmi A, Hakim W, Watanabe A, Zipprich A, Groszmann R . Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition. Hepatology. 2008; 49(1):185-94. PMC: 3129263. DOI: 10.1002/hep.22589. View

Watanabe A, Hashmi A, Gomes D, Town T, Badou A, Flavell R . Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology. 2007; 46(5):1509-18. DOI: 10.1002/hep.21867. View

Hasko G, Szabo C, Nemeth Z, Kvetan V, Pastores S, Vizi E . Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J Immunol. 1996; 157(10):4634-40. View

Csoka B, Selmeczy Z, Koscso B, Nemeth Z, Pacher P, Murray P . Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J. 2011; 26(1):376-86. PMC: 3250237. DOI: 10.1096/fj.11-190934. View

Roman J, Ritzenthaler J, Fenton M, Roser S, Schuyler W . Transcriptional regulation of the human interleukin 1beta gene by fibronectin: role of protein kinase C and activator protein 1 (AP-1). Cytokine. 2000; 12(11):1581-96. DOI: 10.1006/cyto.2000.0759. View

Franchi L, Eigenbrod T, Nunez G . Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol. 2009; 183(2):792-6. PMC: 2754237. DOI: 10.4049/jimmunol.0900173. View

Sanz J, Di Virgilio F . Kinetics and mechanism of ATP-dependent IL-1 beta release from microglial cells. J Immunol. 2000; 164(9):4893-8. DOI: 10.4049/jimmunol.164.9.4893. View

Rock K, Latz E, Ontiveros F, Kono H . The sterile inflammatory response. Annu Rev Immunol. 2010; 28:321-42. PMC: 4315152. DOI: 10.1146/annurev-immunol-030409-101311. View

Eltzschig H, Sitkovsky M, Robson S . Purinergic signaling during inflammation. N Engl J Med. 2012; 367(24):2322-33. PMC: 3675791. DOI: 10.1056/NEJMra1205750. View

10.

Ohta A, Sitkovsky M . Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature. 2002; 414(6866):916-20. DOI: 10.1038/414916a. View

11.

Hu C, Wang L, Chodosh L, Keith B, Simon M . Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003; 23(24):9361-74. PMC: 309606. DOI: 10.1128/MCB.23.24.9361-9374.2003. View

12.

Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S . IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007; 117(12):3786-99. PMC: 2066195. DOI: 10.1172/JCI32285. View

13.

Nemeth Z, Leibovich S, Deitch E, Vizi E, Szabo C, Hasko G . cDNA microarray analysis reveals a nuclear factor-kappaB-independent regulation of macrophage function by adenosine. J Pharmacol Exp Ther. 2003; 306(3):1042-9. DOI: 10.1124/jpet.103.052944. View

14.

Ahn S, Olive M, Aggarwal S, Krylov D, Ginty D, Vinson C . A dominant-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos. Mol Cell Biol. 1998; 18(2):967-77. PMC: 108809. DOI: 10.1128/MCB.18.2.967. View

15.

Lukashev D, Ohta A, Apasov S, Chen J, Sitkovsky M . Cutting edge: Physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. J Immunol. 2004; 173(1):21-4. DOI: 10.4049/jimmunol.173.1.21. View

16.

Roth S, Park S, Sikorski C, Osinski J, Chan R, Loomis K . Concentrations of adenosine and its metabolites in the rat retina/choroid during reperfusion after ischemia. Curr Eye Res. 1997; 16(9):875-85. DOI: 10.1076/ceyr.16.9.875.5045. View

17.

Hasko G, Linden J, Cronstein B, Pacher P . Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008; 7(9):759-70. PMC: 2568887. DOI: 10.1038/nrd2638. View

18.

Fujihara M, Muroi M, Tanamoto K, Suzuki T, Azuma H, Ikeda H . Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol Ther. 2003; 100(2):171-94. DOI: 10.1016/j.pharmthera.2003.08.003. View

19.

Zhang W, Petrovic J, Callaghan D, Jones A, Cui H, Howlett C . Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures. J Neuroimmunol. 2006; 174(1-2):63-73. DOI: 10.1016/j.jneuroim.2006.01.014. View

20.

Martinon F, Mayor A, Tschopp J . The inflammasomes: guardians of the body. Annu Rev Immunol. 2009; 27:229-65. DOI: 10.1146/annurev.immunol.021908.132715. View