Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration

Tanuja Chitnis, Jaime Imitola, Yue Wang, Wassim Elyaman, Prianka Chawla, Maia Sharuk, Khadir Raddassi, Roderick T. Bronson, Samia J. Khoury

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

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). Wlds mice have a triplication of the fusion gene Ube4b/Nmnat and a phenotype of axon protection. Wlds 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 Wlds 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 Wlds mice. Administration of blocking anti-CD200 antibody to Wlds mice abrogated disease attenuation and was associated with increased CNS inflammation and neurodegeneration. In vitro, Wlds 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.

Original languageEnglish
Pages (from-to)1695-1712
Number of pages18
JournalAmerican Journal of Pathology
Volume170
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

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