Adenosine receptor involvement in both the initiation and resolution of inflammation in the central nervous system during experimental autoimmune encephalomyelitis (54.6)

Abstract

Abstract Extracellular adenosine is a key regulator of inflammatory immune responses. Utilizing the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis, we have shown that both the lack of CD73 (catalyzes extracellular adenosine) and antagonist blockade of the A2A adenosine receptor (AR) can protect mice from EAE development. To fully define the importance of A2AAR signaling during EAE progression, we induced disease in A2AAR-/- mice. Surprisingly, A2AAR-/- mice were not only susceptible to EAE, but developed more severe disease associated with an increased number of brain and spinal cord lymphocytes and activated microglial cells. Severe EAE was also found in radiation bone marrow chimeric mice given stem cells from A2AAR-/- donor mice. However, irradiated A2AAR-/- mice given wild type donor cells were protected from disease progression. Our data strongly suggests that A2AAR expression on lymphocytes is important in controlling the magnitude of the inflammatory response during EAE, as A2AAR-/- lymphocytes had a higher proliferative potential and produced more IFNγ following MOG stimulation compared to those from wild type mice. However, A2AAR signaling on non-hematopoietic cells also has an important role in promoting disease progression as A2AAR blockade prevented EAE development in T cell deficient mice given A2AAR-/- donor cells. Overall, our results indicate that A2AAR signaling is involved in both the progression and resolution of EAE.