Extracellular adenosine as a master regulator of immune cell migration into the central nervous system via induction of CX3CL1 (60.9)

Abstract

Abstract Having the ability to modulate lymphocyte entry into the central nervous system (CNS) would benefit patients with neuroinflammatory diseases. We have previously shown that extracellular adenosine regulates CNS entry of lymphocytes during experimental autoimmune encephalomyelitis (EAE), the animal model for the CNS inflammatory disease multiple sclerosis. For instance, while extracellular adenosine levels are vastly increased following inflammatory cellular damage (from the hydrolysis of released cytoplasimic ATP by CD39 and CD73), mice lacking CD73 or given adenosine receptor (AR) antagonists have significantly reduced CNS lymphocyte entry during EAE. We now show through detailed genetic studies that AR signaling regulates lymphocyte migration into the CNS though induction of CX3CL1, a specialized chemokine that acts as both an adhesion molecule and chemoattractant for lymphocytes, monocytes, and NK cells. We show that AR signaling is necessary and sufficient to induce CNS expression of CX3CL1 (as compared to over 40 other chemokines and adhesion molecules). AR regulation of CX3CL1 is critical for EAE progression, as daily anti-CX3CL1 treatments prevent CNS lymphocyte infiltration during EAE. Importantly, AR signaling induces CX3CL1 expression on the choroid plexus, a known CNS entry point for lymphocytes. As AR signaling can promote lymphocyte transmigration across a choroid plexus transwell barrier, we conclude that adenosine is a master regulator of CNS lymphocyte entry.