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Adenosine 2a receptor signaling in autoimmune neuroinflammation

Graf, J;

Background & Hypothesis: Adenosine is known to play an anti-inflammatory role in
the immune system. Previous studies implicate that ligation of this purine
nucleoside to the adenosine 2a receptor (A2aR) unfolds the key mechanism for its
immunomodulatory impact. However, possible immune-related effects in the
central nervous system (CNS) remain unclear, particularly in autoimmune neuroinflammation.
Methods: With my work I clinically and histologically investigated the effect of
A2aR signaling in the experimental autoimmune encephalomyelitis (EAE) model of
multiple sclerosis (MS) in mice. Using genetic deletion and both pharmacological
activation and inactivation of the A2aR, I analysed the functional motor impairment
and the extent of tissue alterations in brain and spinal cord. These tissue
alterations were investigated using immunohistochemistry, the key tool for
visualizing morphological changes on cellular level. This technique is capable of
showing immune cell infiltration, demyelination and the extent of tissue
destruction. In order to confirm the myelin-related damage patterns, I also
performed Oil-Red-O lipid staining. In addition to EAE, I used lipopolysaccharide
(LPS)-based experiments which allowed an investigation of microglia without
contamination of peripheral macrophages.
Results: In line with the well-investigated anti-inflammatory effect of A2aR, mice
lacking the A2aR (A2aR-/-
) developed exacerbated disease scores in the early
phase of disease with more and larger CNS lesions and increased T cell infiltration
compared to their wild type litter mates. However, in the late phase of disease the
clinical scores of wild type and knock out mice were comparable, but leaving the
wild type mice with larger lesions, stronger tissue destruction and slightly
increased T cell infiltration. Interestingly, injecting mice with the specific A2aR
agonist CGS-21680 in already developed EAE also resulted in more and larger
lesions, an increased inflammatory cell infiltration and a higher mean clinical
score. I was able to reproduce the visualisation of myelin damage with the OilRed-O lipid staining. Inactivating the A2aR with its specific antagonist SCH-58261
leads to less and smaller lesions in comparison with the control group. A later
onset of disease and a milder clinical outcome were also observed. With the LPS
injection model it was shown that triggering the A2aR causes in vivo microglial
activation.
Conclusions: Taken together, the results indicate that activation of the A2aR in the
early phase of EAE has a positive impact on the outcome of the disease.
Nevertheless, a continuous activation of the receptor results in unfavourable
clinical and histological findings. Apparently, activation of the A2aR has a
detrimental effect in established neuroinflammation.