A3 Adenosine Receptor in Rheumatoid Arthritis: Friend or Foe? A Key Mediator of Different Signaling Pathways.

INTRODUCTION Rheumatoid Arthritis (RA) is an autoimmune disease that has heterogeneous clinical manifestations. The A3 Adenosine Receptor (A3AR), a protein implicated in numerous inflammatory pathways, is overexpressed in patients with RA.

Methods

The available preclinical and clinical literature about A3AR signaling in RA was reviewed, and published data on its molecular pathways, immunomodulatory functions, and role in synovial fibroblasts were searched. Studies exploring A3AR agonists and their mechanistic interactions with NF-κB and p53 pathways were also reviewed.

Results

The mechanisms in which the A3AR is involved in alleviating inflammatory status resulting from alterations in transcriptional activity of the nuclear factor kappa B-light- chain-enhancer of activated inflammatory cells (NF-κB) in RA and the clinical and preclinical studies working on A3AR agonists alongside the apoptosis process by interacting with the p53 expression level. In contrast, we explained that the canonical and non-canonical pathways for A3AR, which may lead to worsening inflammation, were detailed.

Discussion

The implication of A3AR in the worsening of destructive effects on RA synovium in cases of hypoxia, as well as the consequences of low oxygen levels on FLSs, was detailed.

Conclusion

In conclusion, we hypothesized that the overexpressed A3AR could provide the activation of Ras, leading to the inflammatory and senescent phenotype of FLSs during the pathological processes in RA.