Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor

Gillian R Milne,Timothy M Palmer

doi:10.1100/tsw.2011.22

Gillian R Milne, Timothy M Palmer

Open Access

https://doi.org/10.1100/tsw.2011.22

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Journal: TheScientificWorldJournal	Publication Date: Jan 1, 2011
Citations: 234	License type: CC BY 3.0

Affiliation: University of Glasgow

Abstract

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, A2A, A2B, and A3, of which the A2A adenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR 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 A2AAR 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 A2AAR 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 A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

Highlights

Adenosine is a ubiquitous purine nucleoside that accumulates extracellularly in response to metabolic stresses such as hypoxia and inflammation
A substantial body of evidence has demonstrated that important cell types, such as eosinophils and mast cells, express specific combinations of these receptors, and several studies have suggested that pharmacological blockade of the A2B and A3 subtypes may be of particular benefit in attenuating the eosinophil trafficking, lung fibrosis, and chronic inflammation responsible for chronic obstructive pulmonary disease (COPD) and asthma[1]
Most attention has been devoted to the A2A adenosine receptor (A2AAR), which is expressed on most lymphoid cells, allowing it to regulate numerous aspects of the immune response, where it fulfils a predominantly anti-inflammatory role

Summary

INTRODUCTION

Adenosine is a ubiquitous purine nucleoside that accumulates extracellularly in response to metabolic stresses such as hypoxia and inflammation It exerts a wide range of physiological effects via ligation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3. Most attention has been devoted to the A2A adenosine receptor (A2AAR), which is expressed on most lymphoid cells, allowing it to regulate numerous aspects of the immune response, where it fulfils a predominantly anti-inflammatory role. This has been demonstrated through numerous in vitro and in vivo studies using A2AAR-selective agonists to suppress inflammation and by observation of enhanced inflammatory responses in A2AAR-deficient mice[1,2,3,4]. We review data obtained in studies investigating the effect of A2AAR activation or inactivation in different tissues in animal models of inflammatory disease

HOW IS ADENOSINE PRODUCED IN VIVO?

SUPPRESSION OF INFLAMMATORY RESPONSES IN VITRO

General Mechanisms