Neurons promote encephalitogenic CD4(+) lymphocyte infiltration in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, leading to demyelination and axonal degeneration. Neuronal excitotoxity mediated by Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) results in neuronal damage in experimental autoimmune encephalitis (EAE), an animal model of MS. Here, we define a critical role of excitatory neurons in the pathogenesis of CD4(+) lymphocyte accumulation in EAE. We silenced the activity of excitatory neurons in a mouse model of targeted EAE using inhibitory designer receptors exclusively activated by designer drugs (DREADD) under a CaMKIIα promoter. Neuronal silencing mitigated clinical disease scores in EAE, reduced the expression of c-fos, Tnfα, Ccl2, and Ccr2 mRNAs in targeted EAE lesions, and prevented the migration of CD4(+) lymphocytes towards neurons. Ccl2 shRNA treatment of targeted EAE suppressed the migration of CD4(+) lymphocytes and alleviated the motor deficits of EAE. Our findings indicate that neuronal activation in EAE promotes the migration of CCR2(+) CD4(+) lymphocytes and that neuronal silencing with an inhibitory DREADD alleviates clinical and molecular markers of disease. Neuronal CCL2 is thought to be involved in promoting lymphocytes migration.