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Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients.

ABSTRACT: A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression in the hippocampus, comprising WML and GML,of post-mortem MS patients, and of control subjects. CCL2 and CCR2 mRNA were significantly increased in demyelinated MS hippocampus. Semi-quantification of CCL2 and CCR2 immunoreactivity showed that CCL2 is present in astrocytes only in active WML. CCR2 is upregulated in monocytes/macrophages or amoeboid microglia in active WML, and in ramified microglia in active GML, although to a lesser extent. As a follow-up, we observed a significantly increased CCL2 production by WM-, but not GM-derived astrocytes upon stimulation with bz-ATP in vitro. Finally, upon CCL2 stimulation, GM-derived microglia significantly increased their proliferation rate. We conclude that within hippocampal lesions, CCL2 expression is mainly restricted to WML, whereas the receptor CCR2 is upregulated in both WML and GML. The relative absence of CCL2 in GML may explain the lack of infiltrating immune cells in this type of lesions. We propose that the divergent expression of CCL2 and CCR2 in WML and GML explains or contributes to the differences in WML and GML formation in MS.

SUBMITTER: Prins M

PROVIDER: S-EPMC4158064 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients.

Prins Marloes M Dutta Ranjan R Baselmans Bart B Brevé John J P JJ Bol John G J M JG Deckard Sadie A SA van der Valk Paul P Amor Sandra S Trapp Bruce D BD de Vries Helga E HE Drukarch Benjamin B van Dam Anne-Marie AM

Acta neuropathologica communications 20140823

A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression i ...[more]

PMID: 25149422

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Project description:Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and under pathologic conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples, to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibers, and relate differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibers was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive vs mature oligodendrocytes) is more significant than by region but segregation for each cell type by region is apparent. Molecular features of grey matter versus white matter derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter derived cells with relevance for myelination included those related to responses to external environment, cell-cell communication, cell migration, and cell adhesion. Immune and cell death related genes were up-regulated in grey matter derived cells. We observed a significant number of up-regulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, likely reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.

Dataset Information

Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients.

Publications

Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients.

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