Adenosine is a potent modulator that has a tremendous effect on the immune system. Adenosine affects T cells activity, and necessary in maintaining T helper/Tregs ratio. Adenosine signalling is also involved in activating neutrophils and the formation of neutrophil extracellular traps (NETs), which has been linked to autoimmune disorders. Therefore, adenosine, through its receptors, is very important in maintaining homeostasis and involved in the development of autoimmune diseases. In this study, we aim to evaluate the role of adenosine A1 and A2A receptors in involvement of autoimmune diseases. we studied adenosine regulation by NETosis in vitro, and we used two murine models of autoimmune diseases: Type I diabetes mellitus (T1DM), induced by low-dose streptozotocin and pristane-induced systemic lupus erythematosus (SLE). We have found that A R enhances and A R suppresses NETosis. In addition, in both models, A R-KO mice were predisposed to the development of autoimmunity. In SLE model, in WT mice, 6h after pristane injection we observed decline of A R mRNA levels, that was in parallel to lymphocytes reduction. Following pristane 43% of A R-KO mice suffered from lupus-like disease while WT mice remained without any sign of disease at 36 weeks. In WT mice, at 10 days A R mRNA levels were significantly higher compared to A1R-KO mice. Similar to SLE, in T1DM model the presence of A R and A R was protective. Our data suggest that in autoimmune diseases, the acute elimination of lymphocytes and reduction of DNA release due to NETosis depends on A R desensitization and long-term suppression of A R.
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