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Theiler's murine encephalomyelitis virus induces a demyelinating disease (TMEV-IDD) of the central nervous system (CNS) in susceptible mouse strains with accompanying histopathology characterized by mononuclear cell infiltrates. In susceptible strains of mice such as SJL, virus establishes a persistent infection in macrophages, induces a CNS infiltration by macrophages, T cells, and B cells, which results in chronic-progressive paralysis. In the present report the authors have investigated the functional role of CCL2 (monocyte chemotactic protein-1) in the induction and progression of demyelinating disease. Treatment of infected mice at day 0, 14, or 28 with anti-CCL2 resulted in a significant decrease in the clinical disease progression. Further analysis of anti-CCL2–treated mice revealed decreased CNS inflammation and mononuclear cell infiltration with an accompanying change in inflammatory cytokine responses. There was an overall decrease in the absolute numbers of CNS-infiltrating CD4+ T cells, macrophages, and B cells. Finally, anti-CCL2 treatment resulted in decreased viral load in the CNS. These data directly demonstrate a role for CCL2 in the pathogenesis of TMEV-IDD.

Theiler's murine encephalomyelitis virus is an endemic murine pathogen that induces a demyelinating disease of the central nervous system in susceptible mouse strains. The disease is characterized by central nervous system mononuclear cell infiltration and presents as chronic, progressive paralysis. The expression of CC and C-x-C chemokines in the central nervous system of Theiler's murine encephalomyelitis virus-infected mice was examined throughout the disease course by ELISA and RT - PCR analysis. Central nervous system expression of MCP-1 and MIP-1alpha protein was evident by day 11 post Theiler's murine encephalomyelitis virus infection of SJL mice and continued throughout disease progression. MIP-1alpha, RANTES, MCP-1, C10, IP-10, and MIP-1beta mRNA was specifically expressed in the central nervous system and not the periphery following Theiler's murine encephalomyelitis virus infection. This was associated with development of clinical disease. These data suggest that the expression of multiple chemokines at particular times following viral infection is associated with demyelinating disease.

CCL2 is a member of the CC chemokine family that mediates the migration and recruitment of monocytes and T cells and has been identified in the central nervous system (CNS) during several neuroinflammatory diseases. In order to examine the biological effect of constitutive CCL2 expression in the CNS, the authors engineered a mouse that expressed CCL2 in the CNS under control of the human glial fibrillary acidic protein (hGFAP) promoter. The results demonstrated that transgenic expression of CCL2 in the CNS resulted in diffuse CNS monocyte infiltration and accumulation. Transgenic CCL2 expression did not alter normal development, differentiation, or function of T cells. There was no evidence of overt CNS disease or other pathologic phenotype when mice were left unchallenged with antigen or uninfected. However, when CCL2 transgenic mice were given a peripheral challenge of lipopolysaccharide (LPS), an inflammatory infiltrate with organized perivascular lesions developed. Infection of the transgenic mice with Theiler’s murine encephalomyelitis virus (TMEV) resulted in accelerated onset and increased severity of clinical and histological disease. These results suggest that CCL2 expression in the CNS is a major pathogenic factor that drives macrophage accumulation in the development of CNS inflammatory disease.

Chemokines and their receptors are large families of inflammatory molecules responsible for a number of biologic functions including the accumulation of leukocytes at tissue sites. Over the past 8 years, a number of studies have indicated a role for chemokines in the pathogenesis of CNS inflammatory diseases. This minireview provides a brief summary of our current knowledge of chemokines and CNS inflammatory diseases including experimental autoimmune encephalomyelitis, multiple sclerosis, virus-induced demyelinating diseases, Alzheimer's disease, and central nervous system bacterial-induced diseases.

(1999). Chemokine regulation of inflammatory-mediated nervous system diseases. Journal of Neurovirology: Vol. 5, No. 1, pp. 1-2.