Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration.
Axonal damage secondary to inflammation is likely the substrate of chronic disability in multiple sclerosis and is found in the animal model of experimental autoimmune encephalomyelitis (EAE). Wld(s) mice have a triplication of the fusion gene Ube4b/Nmnat and a phenotype of axon protection. Wld(s) mice develop an attenuated disease course of EAE, with decreased demyelination, reduced axonal pathology, and decreased central nervous system (CNS) macrophage and microglial accumulation. We show that attenuated disease in Wld(s) mice was associated with robust constitutive expression of the nonsignaling CD200 molecule on neurons in the CNS compared with control mice. CD200 interacts with its signaling receptor CD200R, which we found to be expressed on microglia, astrocytes, and oligodendrocytes at similar levels in control and Wld(s) mice. Administration of blocking anti-CD200 antibody to Wld(s) mice abrogated disease attenuation and was associated with increased CNS inflammation and neurodegeneration. In vitro, Wld(s) neuronal cultures were protected from microglial-induced neurotoxicity compared with control cultures, but protection was abrogated by anti-CD200 antibody. The CD200-CD200R pathway plays a critical role in attenuating EAE and reducing inflammation-mediated damage in the CNS. Strategies that up-regulate the expression of CD200 in the CNS or molecules that ligate the CD200R may be relevant as neuroprotective strategies in multiple sclerosis.
Chitnis
Tanuja
T
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA. tchitnis@rics.bwh.harvard.edu
Imitola
Jaime
J
Wang
Yue
Y
Elyaman
Wassim
W
Chawla
Prianka
P
Sharuk
Maia
M
Raddassi
Khadir
K
Bronson
Roderick T
RT
Khoury
Samia J
SJ
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D015153:Blotting, Western; D049109:Cell Proliferation; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000276:immunology / Q000503:physiopathology*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology
D015703:Antigens, CD; C492346:CD200 receptor, mouse; D015850:Interleukin-6; D007378:Interleukins; D008562:Membrane Glycoproteins; C422042:interleukin 20; C042739:antigens, CD200