Cutting Edge: Physiologic Attenuation of Proinflammatory Transcription by the Gs Protein-Coupled A2A Adenosine Receptor In Vivo

Abstract

The A2A adenosine receptor plays a critical role in the physiologic immunosuppressive pathway that protects normal tissues from excessive collateral damage by overactive immune cells and their proinflammatory cytokines. In this study, we examine and clarify the mechanism of tissue protection by extracellular adenosine using A2AR-deficient mice and show that the A2AR inhibits TLR-induced transcription of proinflammatory cytokines in vivo. The observed increase in proinflammatory cytokines mRNA in A2AR-deficient mice was associated with enhanced activity of the NF-κB transcription factor. These observations provide the genetic in vivo evidence for attenuation of proinflammatory transcriptional activity of NF-κB by a “metabokine” adenosine and point to the need to re-evaluate the regulation of other transcription factors in hypoxic and adenosine-rich microenvironments of inflamed normal tissues and solid tumors.

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

“…In vivo observations suggest marked expansion of this signalling in intact myocardium [41,42], contrasting in vitro evidence that cardiomyocyte NFκB and IκB kinase signalling is only transiently LPS responsive [43]. Importantly, these paths are inhibited by A 2A Rs in other cells, with exogenous agonism decreasing [44,45] and A 2A R KO increasing NFκB activity [6]. Nonetheless, these paths can also promote myocardial stress-resistance and survival under conditions that include inflammatory cytokine challenge [46][47][48].…”

“…myocardial injury [1,2] is not only fundamentally important but also reveals targets for manipulating outcomes. In this regard, adenosine 2A receptors (A 2A Rs) may fulfil a broadly suppressive role to limit inflammatory injury in multiple tissues [3][4][5][6] and enhance myocardial resistance to ischaemic/hypoxic insult, presenting a potentially useful therapeutic target [3,7]. In heart, this G protein-coupled receptor (GPCR) influences coronary tone and angiogenesis, cardiac contractility, fibroblast growth and fibrosis and may mediate protection via ischaemic pre-and postconditioning [8][9][10].…”

“…Transcriptomic interrogation can reveal elements of these complex responses, though there are f e w a n a l y s e s o f m y o c a r d i a l [ 4 1 , 4 2 , 4 9 ] or cardiomyocyte [43,49] responses to endotoxin/sepsis. Approximately 15 % of the 25,646 transcripts expressed in murine hearts were modified in endotoxemia (Table S4), encompassing a multiplicity of canonical paths and functions (Tables 5, S5-S7 [6].…”

Adenosine in fibrosis

“…Occupancy of adenosine A 2A receptors on monocytes inhibits cytokine production [tumor necrosis factor-alpha (TNF- α ), interleukin (IL)-6, IL-8, and IL-12] and enhances release of the anti-inflam-matory cytokine IL-10 [14, 17, 32, 35–40]. Adenosine, acting at A 2 receptors (probably originally misidentified as A 2B receptors), inhibits inhibitory- κ B (I κ B) kinase and nuclear factor- κ B (NF κ B) translocation to the nucleus, a central step in the pathogenesis of inflammation [41, 42]. In murine cells A 3 receptors also downregulate inflammatory cytokine secretion.…”

Le neutrophile : ennemi ou ami ?

“…En effet, l'augmentation de l'AMP cyclique intracellulaire, indépendamment de l'activation du récepteur, mime les effets inhibiteurs de l'adénosine, notamment l'augmentation de l'expression de COX-2 [26]. La signalisation enclenchée par l'AMP cyclique passe en général par l'activation du facteur de transcription CREB (cAMP responsive element binding protein) via sa phosphorylation par la protéine kinase A ; CREB pouvant activer directement la transcription de gènes en se fixant sur leur région promotrice contenant un CRE (cAMP response element) ou en inhiber indirectement d'autres en bloquant le facteur de transcription NF-κB (nuclear factor-κB) qui contrôle la transcription de nombreuses cytokines pro-inflammatoires (TNF-α, par exemple) [34]. L'AMP cyclique active également les enzymes p38, PI3K et ERK1/2 [35].…”