Adenosine A2A Receptor Signaling in the Immunopathogenesis of Experimental Autoimmune Encephalomyelitis

Abstract

Our increasing appreciation of adenosine as an endogenous signaling molecule that terminates inflammation has generated excitement regarding the potential to target adenosine receptors (ARs) in the treatment of multiple sclerosis (MS), a disease of chronic neuroinflammation. Of the four G protein-coupled ARs, A2ARs are the principal mediator of adenosine's anti-inflammatory effects and accordingly, there is a growing body of evidence surrounding the role of A2ARs in experimental autoimmune encephalomyelitis (EAE), the dominant animal model of MS. Such evidence points to a complex, often paradoxical role for A2ARs in the immunopathogenesis of EAE, where they have the ability to both exacerbate and alleviate disease severity. This review seeks to interpret these paradoxical findings and evaluate the therapeutic promise of A2ARs. In essence, the complexities of A2AR signaling arise from two properties. Firstly, A2AR signaling downregulates the inflammatory potential of TH lymphocytes whilst simultaneously facilitating the recruitment of these cells into the CNS. Secondly, A2AR expression by myeloid cells - infiltrating macrophages and CNS-resident microglia - has the capacity to promote both tissue injury and repair in chronic neuroinflammation. Consequently, the therapeutic potential of targeting A2ARs is greatly undermined by the risk of collateral tissue damage in the periphery and/or CNS.

Keywords: adenosine; adenosine 2A receptor; experimental autoimmune encephalomyelitis; microglia; multiple sclerosis; neuroinflammation.

Figure 1

(A) Extracellular adenosine accumulates via the breakdown of ATP, both intracellularly and extracellularly. (B) A2ARs signal predominantly via the adenylate cyclase-cAMP-protein kinase A (PKA) canonical pathway (10). PKA phosphorylates the transcription factor CREB on serine residue 133; activated CREB can affect gene expression directly, via specific promoters, or indirectly, via an important cofactor, CBP. cAMP can also signal directly via the exchange factor Epac.