Role and Function of A2A and A₃ Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis.

Annalisa Ravani,Alessandra Bortoluzzi,Stefania Gessi,Pier Borea,Stefania Merighi,Katia Varani,Silvia Pasquini,Marcello Govoni,Fabrizio Vincenzi,Melissa Padovan

doi:10.3390/ijms18040697

Annalisa Ravani, Alessandra Bortoluzzi + Show 8 more

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https://doi.org/10.3390/ijms18040697

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Abstract

Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA.

Highlights

The purine nucleoside adenosine has been identified as a major local tissue function regulator, when cellular energy supply fails to meet demand [1]
Clinical data included: (i) age, disease duration, gender, serological parameters including rheumatoid factor (RF) and anti-citrullinated cyclic peptide (ACPA); (ii) Disease Activity Score evaluated in 28 joints (DAS28); (iii) functional status as assessed by Health Assessment Questionnaire (HAQ); (iv) pharmacological therapy as comedication with DMARDs such as methotrexate and leflunomide
The study was approved by the local Ethics Committee (Approval No 378, February 2010) of the University Hospital of Ferrara (Italy) and informed consent was obtained from each participant in accordance with the principles outlined in the Declaration of Helsinki

Summary

Introduction

The purine nucleoside adenosine has been identified as a major local tissue function regulator, when cellular energy supply fails to meet demand [1]. Adenosine interacts with four different receptor subtypes, named as A1, A2A, A2B and A3 adenosine receptors (ARs), that belong to the G-protein coupled receptor superfamily [2]. A1 and A3 receptors are negatively coupled to adenylate cyclase and exert an inhibitory effect on cyclic adenosine monophosphate (cAMP) production, whilst A2A and A2B receptors stimulate adenylate cyclase activity by increasing cAMP accumulation [3,4]. Several papers have suggested the involvement of adenosine in inflammatory status by A2A and A3AR activation. Altered expression of A2A and A3ARs has been found in different inflammation-related pathologies highlighting the potential role of these receptors as therapeutic targets in inflammatory diseases [8,9,10]

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