CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice

Abstract

Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5−/−) mice. CCR5−/− and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5−/− mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5−/− mice. Moreover, levels of IL-1β, TNF-α, IFN-γ and MCP-1 cytokine levels were decreased in CCR5−/− mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5−/− mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS.

Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis

“…Although chemokine receptors are normally upregulated in differentiating T cells, enabling them to migrate and home to the location of ongoing immune responses, CCL2 and CCL4 have been detected at high levels in the cerebrospinal fluid, brain tissue, and active lesions of patients with MS, and elevated expression of both chemokine receptors on pathogenic CD4 + T cells has been correlated with the active phase of MS (57,65,66). In fact, the role of CCR2 and CCR5 in pathogenic CD4 + T cell trafficking to the CNS in MS has been confirmed in EAE using receptor-deficient mice (56,59). Although the observed dysregulation of these receptors could be indirectly resulting from the let-7-mediated inhibition of pathogenic Th17 differentiation, we found that the mRNA sequences of both chemokine receptors contain potential let-7 miRNA binding sites.…”

“…Antigen-stimulated T cells upregulate chemokine receptors to sense, migrate, and home to the location of inflammatory sites by following gradients of chemokines (55). Two chemokine receptors, CCR2 and CCR5, have been shown to be critical for the migration of pathogenic T cells to the CNS and subsequently for EAE development (56)(57)(58)(59). To determine whether let-7 regulates CCR2 and CCR5 expression, we measured Ccr2 and Ccr5 mRNA levels in in vitro-generated 2D2Rag2KO pathogenic Th17 cells from WT, Let-7Tg and Lin28Tg mice.…”

CD8+ T Cells in the Central Nervous System of Mice With Herpes Simplex Infection are Highly Activated and Express High Levels of CCR5 and CXCR3

“…Studies in gene-de cient mice show that albeit CCR5 de ciency is associated with exacerbated CNS disease, it does not affect CD8 + T cell numbers in the CNS, neither during HSV-2 infection nor during intracranial infection with coronavirus (24,25). This is in contrast to studies on non-viral CNS in ammation where CCR5 de ciency leads to an attenuated in ux of CD8 + T cells and other immune cells to the spinal cord (26,27). Many ligands for CCR5 are however expressed in the HSV-2-infected spinal cord.…”

Clozapine reduces infiltration into the CNS by targeting migration in experimental autoimmune encephalomyelitis

“…CCR2 −/− mice immunized with MOGp35-55 failed to develop mononuclear cell inflammatory infiltrates in the CNS and failed to increase CNS levels of the chemokines, MCP-1, and interferon (IFN)-inducible protein 10 (IP-10) as well as CCR1, CCR2, and CCR5 [46]. Additionally, deficiency in CCR5 suppresses EAE in C57BL/6 mice by reduced immune cells infiltration and astrocyte and microglia activation [47]. However, our work revealed that the block in migration was not mediated by changes in the expression of CCR2 and CCR5 on immune cells in the blood of EAE animals where we saw an overall reduction of CCR2 and CCR5 on neutrophils compared to healthy animals, but no difference with clozapine treatment.…”