Abstract
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.