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Innate Immune Responses in CNS Inflammation

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Front. Immunol. | doi: 10.3389/fimmu.2018.00402

Adenosine A2a receptor signalling in the immunopathogenesis of Experimental Autoimmune Encephalomyelitis

  • 1Lincoln College, University of Oxford, United Kingdom

Our increasing appreciation of adenosine as an endogenous signalling molecule that terminates inflammation has generated excitement regarding the potential to target adenosine receptors in the treatment of Multiple Sclerosis, a disease of chronic neuroinflammation. Of the four G protein-coupled adenosine receptors (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, 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 signalling arise from its capacity to downregulate the inflammatory potential of TH lymphocytes whilst simultaneously facilitating the recruitment of these cells into the CNS and additionally, from the capacity of A2AR signalling in myeloid cells – infiltrating macrophages and CNS-resident microglia - 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 (EAE), Multiple Sclerosis, Neuroinflammation, Microglia

Received: 23 Oct 2017; Accepted: 13 Feb 2018.

Edited by:

David Pitt, Department of Neurology, Yale School of Medicine, United States

Reviewed by:

Rodrigo A. Cunha, University of Coimbra, Portugal
Christopher Linington, University of Glasgow, United Kingdom
Daniel McKim, The Ohio State University, United States  

Copyright: © 2018 Rajasundaram. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Skanda Rajasundaram, University of Oxford, Lincoln College, Turl Street, Oxford, OX1 3DR, Oxfordshire, United Kingdom, skanda.rajasundaram@lincoln.ox.ac.uk