Chitnis Tanuja, Imitola Jaime, Wang Yue, Elyaman Wassim, Chawla Prianka, Sharuk Maia, Raddassi Khadir, Bronson Roderick T, Khoury Samia J
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
Am J Pathol. 2007 May;170(5):1695-712. doi: 10.2353/ajpath.2007.060677.
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.
炎症继发的轴突损伤可能是多发性硬化症慢性残疾的基础，并且在实验性自身免疫性脑脊髓炎（EAE）动物模型中也有发现。Wld(s)小鼠的融合基因Ube4b/Nmnat存在三倍体，具有轴突保护表型。Wld(s)小鼠的EAE病程减弱，脱髓鞘减少，轴突病理学改变减轻，中枢神经系统（CNS）巨噬细胞和小胶质细胞积聚减少。我们发现，与对照小鼠相比，Wld(s)小鼠疾病减弱与CNS中神经元上非信号传导性CD200分子的强大组成性表达有关。CD200与其信号受体CD200R相互作用，我们发现对照小鼠和Wld(s)小鼠中，CD200R在小胶质细胞、星形胶质细胞和少突胶质细胞上的表达水平相似。给Wld(s)小鼠注射抗CD200阻断抗体可消除疾病减弱现象，并伴有CNS炎症和神经变性增加。在体外，与对照培养物相比，Wld(s)神经元培养物可免受小胶质细胞诱导的神经毒性，但抗CD200抗体可消除这种保护作用。CD200-CD200R途径在减轻EAE和减少CNS中炎症介导的损伤方面起关键作用。上调CNS中CD200表达的策略或与CD200R结合的分子可能作为多发性硬化症的神经保护策略。
