Tissue damage associated with trauma might release a sufficient autoantigen substrate to break immune tolerance. In a previous study, we showed that the leukopenia observed following severe inflammation is related to adenosine A1-receptor (A1R) desensitization and A2AR upregulation. We hypothesized that, under destructive pathological conditions this mechanism is beneficial in reducing prevalence of autoimmunity. In this study, we aim to evaluate the protective role of A1R and A2AR in prevention of autoimmune diseases. We used two murine models of autoimmune diseases: type 1 diabetes (T1D) induced by low-dose streptozotocin and pristane-induced lupus (PIL) and on neutrophils we studied NETosis regulation by adenosine. In both the T1D and PIL models, A1R-KO mice were predisposed to the development of autoimmunity. In the PIL model, in WT mice, parallel to the decline of A1R mRNA levels, lymphocytes number dropped (-85%) 6h after pristane injection. WT mice remained without any sign of disease at 36 weeks. In contrast, following pristane 43% of A1R-KO mice suffered from lupus-like disease. Compared to A1R-KO, in WT mice at 10 days A2AR mRNA levels were significantly higher. Similar to PIL, in T1D model the presence of A1R and A2AR was protective. In addition, we found that A1R increases and A2AR suppresses NETosis. We suggest that adenosine-dependent immune suppression and reduction in neutrophil extracellular traps (NETs) limits the reactive T-cells and development of anti-double strand DNA (dsDNA) antibodies that promote autoimmunity.