Anti-inflammatory and immunosuppressive effects of the A_2A adenosine receptor

The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A₁, A_2A, A_2B, and A₃, of which the A_2A adenosine receptor (A_2AAR) is recognised as a major mediator of anti-inflammatory responses. The A_2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A_2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A_2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A_2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A_2AAR agonists for use in the clinic to treat specific inflammatory conditions