Adenosine A_2A receptor controls the gateway of the choroid plexus

The choroid plexus (CP) is one of the key gateways regulating the entry of peripheral immune cells into the CNS. However, the neuromodulatory mechanisms of maintaining its gateway activity are not fully understood. Here, we identified adenosine A_2A receptor (A_2AR) activity as a regulatory signal for the activity of CP gateway under physiological conditions. In association with a tightly closed CP gateway, we found that A_2AR was present at low density in the CP. The RNA-seq analysis revealed that the A_2AR antagonist KW6002 affected the expression of the cell adhesion molecules’ (CAMs) pathway and cell response to IFN-γ in the CP. Furthermore, blocking or activating A_2AR signaling in the CP resulted in a decreased and an increased, respectively, expression of lymphocyte trafficking determinants and disruption of the tight junctions (TJs). Furthermore, A_2AR signaling regulates the CP permeability. Thus, A_2AR activity in the CP may serve as a therapeutic target for remodeling the immune homeostasis in the CNS with implications for the treatment of neuroimmunological disorders.