Multiple Sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that affects over one million people worldwide. While the cause ofthis debilitating disease is unknown, our studies utilizing the experimental autoimmune encephalomyelitis (EAE) mouse model for MS strongly suggests that the purine nucleoside adenosine and the signaling of its A2A adenosine receptor (AR) subtype are required for disease development. Specifically, we found that mice that lack the extracellular adenosine catalyzing enzyme, CD73, or that are given antagonists that block A2AAR signaling are protected from EAE. Additionally, we found that CD73 and the A2AAR are highly expressed on the choroid plexus, a CNS structure which controls the passage of lymphocytes from the blood to CSF and has been proposed to be the entry point of autoreactive lymphocytes into the CNS during EAE/MS. We hypothesize that A2AAR signaling at the choroid plexus is required for the entry of lymphocytes into the CNS for EAE/MS disease progression. Therefore, I propose to study how A2AAR signaling regulates EAE progression and lymphocyte infiltration into the CNS. Specifically, I will determine if A2AAR-/- mice are susceptible to EAE. Additionally, I will use adoptive transfer studies to determine if A2AAR signaling is required on lymphocytes or in the CNS for EAE progression. I will use A2AAR antagonist treatments (which are effective at preventing the development of EAE in mice) and attempt to lessen disease in mice that have preexisting EAE or to prevent the onset of EAE relapse. I will also evaluate the consequences of A2AAR signaling on lymphocyte passage into the CNS at the choroid plexus. To accomplish this, I will utilize A2AAR agonists to determine if the lymphocyte migration across an in vitro choroid plexus barrier can be induced. Additionally, I will determine whether A2AAR agonists can alter the expression of cellular and tight junction adhesion molecules on choroid plexus epithelial cells. The results from our studies will provide new insights into how CNS lymphocyte migration is regulated in normal and disease conditions. Our project highly conforms to the NINDS mission to reduce the burden of neurological disease. Relevance: Using the an animal model for multiple sclerosis (MS), we have evidence that adenosine receptor signaling regulates the entry of lymphocytes into the central nervous system (CNS). Our research will provide the basis for development of potential adenosine receptor based therapies aimed at blocking immune cell invasion into the CNS in neuroinflammatory diseases such as MS. Such therapies could be used to stop the progress of, or even possibly reverse the damage caused by MS.
|Mills, Jeffrey H; Alabanza, Leah M; Mahamed, Deeqa A et al. (2012) Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis. J Neuroinflammation 9:193|
|Mills, Jeffrey H; Kim, Do-Geun; Krenz, Antje et al. (2012) A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. J Immunol 188:5713-22|
|Carman, Aaron J; Mills, Jeffrey H; Krenz, Antje et al. (2011) Adenosine receptor signaling modulates permeability of the blood-brain barrier. J Neurosci 31:13272-80|