Multiple Sclerosis (MS) is an inflammatory attack on the central nervous system (CNS) that results in loss of neuronal function and can lead to death. Experimental Autoimmune Encephalomyelitis (EAE) is a mouse model for MS, and like MS, is an autoimmune disease mediated by proinflammatory immune cells that infiltrate the CNS and mount immune responses against myelin components, resulting in neuronal damage that can cause paralysis and even death. CD73 (Ecto-5'-nucleotidase) is a glycosyl phosphatidylinositol (GPI)-linked membrane protein that catalyzes the extracellular dephosphorylation of AMP to adenosine. During an immune response, ATP released from damaged cells is converted to adenosine, mainly through the enzymatic action of CD73. This extracellular adenosine acts as a negative feedback signal to lymphocytes that express adenosine receptors and essentially turns off the immune response to prevent excessive cellular damage. Preliminary evidence shows CD73 generated adenosine is required for efficient lymphocyte migration into the CNS and for EAE development. The goals of this proposal are to 1) determine the role of adenosine signaling in regulating lymphocyte migration into the CNS to cause autoimmune disease;and 2) define the adhesion molecules and chemokines that are regulated by adenosine signaling to influence lymphocyte migration at the choroid plexus. To achieve these goals we will: test the concentration of extracellular adenosine before and during EAE induction in wild type and CD73-/- mice;investigate the expression pattern and level of adenosine receptors in the brain before and during EAE development;determine the consequences of adenosine receptor blockade during EAE on lymphocyte infiltration and disease development;determine whether mice deficient in adenosine receptor signaling are susceptible to EAE induction;determine the effect of adenosine receptor signaling on lymphocyte passage into the CNS, whether blockade of CD73 enzymatic ability can prevent development of EAE in wild type mice or stabilize disease in mice with preexisting EAE;and investigate whether enhancing adenosine degradation with PEG-ADA can prevent development of EAE in wild type mice or stabilize the disease. To define the adhesion molecules and chemokines that are regulated by adenosine signaling to influence lymphocyte migration at the choroid plexus, we will use a mouse choroid plexus cell line to determine whether adenosine signaling at the choroid plexus can trigger lymphocyte migration in vitro;we will quantify the expression of adhesion molecules on the choroid plexus in vitro and during EAE in the presence or absence of adenosine receptor signaling;we will quantify the expression of adhesion molecules on the choroid plexus and lymphocytes in vivo and in vitro in the presence or absence of adenosine receptor signaling. Finally, we will investigate the impact of adenosine receptor signaling on chemokine secretion at the choroid plexus during EAE.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system. It is mediated by infiltration of immune cells into the central nervous system (CNS), causing inflammation which results in damage to neurons, leading to paralysis and even death. EAE is the animal model for MS. We have evidence suggesting that CD73-generated adenosine regulates the entry of lymphocytes into the brains of mice with EAE. This finding provides potential for development of therapies aimed at blocking immune cell invasion of 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.
|Torres, Luisa; Robinson, Sudie-Ann; Kim, Do-Geun et al. (2018) Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer's disease in wild-type, C57BL/6 mice. J Neuroinflammation 15:57|
|Grelotti, David J; Hammer, Gwendolyn P; Dilley, James W et al. (2017) Does substance use compromise depression treatment in persons with HIV? Findings from a randomized controlled trial. AIDS Care 29:273-279|
|Kim, Do-Geun; Krenz, Antje; Toussaint, Leon E et al. (2016) Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 13:1|
|Kim, Do-Geun; Bynoe, Margaret S (2016) A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier. J Clin Invest 126:1717-33|
|Bynoe, Margaret S; Viret, Christophe; Yan, Angela et al. (2015) Adenosine receptor signaling: a key to opening the blood-brain door. Fluids Barriers CNS 12:20|
|Kannan, Arun K; Kim, Do-Geun; August, Avery et al. (2015) Itk signals promote neuroinflammation by regulating CD4+ T-cell activation and trafficking. J Neurosci 35:221-33|
|Kim, Do-Geun; Bynoe, Margaret S (2015) A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability. Mol Neurobiol 52:664-78|
|Alabanza, Leah M; Esmon, Naomi L; Esmon, Charles T et al. (2013) Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells. J Immunol 191:3764-77|
|Alabanza, Leah M; Bynoe, Margaret S (2012) Thrombin induces an inflammatory phenotype in a human brain endothelial cell line. J Neuroimmunol 245:48-55|
|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|
Showing the most recent 10 out of 14 publications