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Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE.

Current multiple sclerosis (MS) therapies only partially prevent chronically worsening neurological deficits, which are largely attributable to progressive loss of CNS axons. Prior studies of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide), a model of MS, documented continued axon loss for months after acute CNS inflammatory infiltrates had subsided, and massive astroglial induction of CCL2 (MCP-1), a chemokine for CCR2(+) monocytes. We now report that conditional deletion of astroglial CCL2 significantly decreases CNS accumulation of classically activated (M1) monocyte-derived macrophages and microglial expression of M1 markers during the initial CNS inflammatory phase of MOG peptide EAE, reduces the acute and long-term severity of clinical deficits and slows the progression of spinal cord axon loss. In addition, lack of astroglial-derived CCL2 results in increased accumulation of Th17 cells within the CNS in these mice, but also in greater confinement of CD4(+) lymphocytes to CNS perivascular spaces. These findings suggest that therapies designed to inhibit astroglial CCL2-driven trafficking of monocyte-derived macrophages to the CNS during acute MS exacerbations have the potential to significantly reduce CNS axon loss and slow progression of neurological deficits.

Pubmed ID: 24920622 RIS Download

Mesh terms: Analysis of Variance | Animals | Astrocytes | Axons | Bacterial Proteins | Central Nervous System | Chemokine CCL2 | Encephalomyelitis, Autoimmune, Experimental | Flow Cytometry | Glial Fibrillary Acidic Protein | Luminescent Proteins | Macrophages | Mice | Mice, Inbred C57BL | Mice, Transgenic | Microscopy, Electron, Transmission | Myelin-Oligodendrocyte Glycoprotein | Peptide Fragments | Proteins

Data used in this publication

Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS025044

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