A2A Adenosine Receptors Are Differentially Modulated by Pharmacological Treatments in Rheumatoid Arthritis Patients and Their Stimulation Ameliorates Adjuvant-Induced Arthritis in Rats

Abstract

A2A adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A2AARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A2AAR stimulation in a rat model of arthritis. We investigated A2AAR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A2AARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A2AAR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A2AAR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A2AAR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A2AAR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A2AAR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A2AARs in lymphocytes from RA patients. The effectiveness of A2AAR stimulation in a rat model of arthritis supported the role of A2AAR agonists as potential pharmacological treatment for RA.

Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination

“…Indeed, previous studies have shown a positive correlation between the number of Tfh cells and disease burden in patients with RA (26). Perhaps consistent with this, A2aR agonists effectively suppress animal models of inflammatory arthritis (27). The fact that the first-line anti-rheumatic drugs methotrexate and sulfasalazine act, in part, through the generation of extracellular adenosine and A2aR signaling (28, 29), lends further support to the notion that A2aR signaling can ameliorate T-dependent B cell autoreactivity.…”

Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases

“…In particular, A 2a is upregulated by agents that stimulate activation of NFκB (a central transcriptional regulator in the inflammatory process), such as TNF, IL-1 and endotoxin, 24-28 and acts, as described below, as a feedback inhibitor of inflammation. Evidence from patients with RA confirms these observations: increased expression of A 2a on peripheral white blood cells in these patients is reduced by treatment with anti-TNF agents 29,30 . In addition to regulation of A 2a expression, TNF and other proinflammatory cytokines increase the function of these receptors by preventing receptor desensitization 31 , further downregulating inflammation.…”

Topical application of the adenosine A2A receptor agonist CGS‐21680 prevents phorbol‐induced epidermal hyperplasia and inflammation in mice

“…Therefore, the inhibition of both NF κ B activation and TNF‐ α release could prevent the proinflammatory positive feedback loop produced by TNF‐ α /NF κ B activation in psoriatic skin. In a similar manner, it has been described that CGS‐21680 reduces the progression of murine type II collagen‐induced arthritis (CIA) and ameliorates adjuvant‐induce arthritis in rats , both accepted animal models of rheumatoid arthritis, which are also characterized by increased levels of TNF‐ α and activation of the NF κ B signalling pathway.…”