Complex regulation of ecto-5'-nucleotidase/CD73 and A2AR-mediated adenosine signaling at neurovascular unit: A link between acute and chronic neuroinflammation.

The review summarizes available data regarding the complex regulation of CD73 at the neurovascular unit (NVU) during neuroinflammation. Based on available data we propose the biphasic pattern of CD73 regulation at NVU, with an early attenuation and a postponed up-regulation of CD73 activity. Transient attenuation of CD73 activity on leukocyte/vascular endothelium and leukocyte/astrocyte surface, required for the initiation of a neuroinflammatory response, may be effectuated either by catalytic inhibition of CD73 and/or by shedding of the CD73 molecule from the cell surface, while postponed induction of CD73 is effectuated by transcriptional up-regulation of Nt5e and posttranslational modifications. Neuroinflammatory conditions are also associated with significant enhancement and gain-of-function of A2AR-mediated adenosine signaling. However, in contrast to the temporary prevalence of A2AR over A1R signaling during an acute inflammatory response, prolonged induction of A2AR and resulting perpetual CD73/A2AR coupling may be a contributing factors in the transition between acute and chronic neuroinflammation. Thus, pharmacological targeting of the CD73/A2AR axis may attenuate inflammatory response and ameliorate neurological deficits in chronic neuroinflammatory conditions.