Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis

T Zeis,O.W Howell,R Reynolds,N Schaeren-Wiemers

doi:10.1016/j.expneurol.2018.03.012

T Zeis, O.W Howell + Show 2 more

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https://doi.org/10.1016/j.expneurol.2018.03.012

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Abstract

Little is known about the decisive molecular factors that regulate lesion remyelination in Multiple Sclerosis. To identify such factors, we performed a differential gene expression analysis of normal appearing white matter (NAWM), active, remyelinating, and inactive demyelinated lesions. As expected, many genes involved in inflammatory processes were detected to be differentially regulated between these tissue types. Among them, we found an increased expression of members of the STAT6 pathway such as STAT6, IL4 and IL4R in active, remyelinated and inactive demyelinated lesions. This suggests that a protective, anti-inflammatory reaction, as already reported to be present in MS NAWM, is further enhanced in lesion tissues. Focusing on genes influencing oligodendrogliogenesis, we found a decreased expression of NKX2-2 in active, remyelinated and inactive demyelinated lesions, whereas SOX10 was downregulated in inactive demyelinated lesions, when compared to NAWM. Simultaneously, CXCL12 (SDF1) expression was strongly increased in active, remyelinated and inactive demyelinated lesions, but increased expression of the IGF1 and IGF2 genes was found in inactive demyelinated lesions. This demonstrates that, in principle, expression of genes promoting oligodendrogliogenesis occurs in MS lesion tissue - even in inactive demyelinated lesions. In contrast, oligodendrogenesis inhibiting genes such as JAG1 were also expressed at higher levels in inactive demyelinated lesions. Both, oligodendrogliogenesis promoting as well as inhibiting genes are expressed in all lesion tissues. However, no clear promoting or inhibiting expression pattern could be detected in any of the different types of lesioned tissues. This might reflect the heterogeneity of lesion development in MS patients, both in terms of mechanisms and temporal differences.

Highlights

Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS) with a large degree of heterogeneity in clinical course and histopathology (Compston and Coles, 2002)
All gene expression data were compared between the different tissue types (Fig. 2, Supporting information Table S1), representative for specific stages in lesion development (Fig. 1)
To identify genes which might be involved in the initiation further development of lesions, we first compared the gene expression patterns between active lesions (AL) and normal appearing white matter (NAWM)

Summary

Introduction

Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS) with a large degree of heterogeneity in clinical course and histopathology (Compston and Coles, 2002). The mechanisms underlying early lesion development are still unclear, but are thought to involve altered BBB permeability and nodules of activated microglial (van der Valk and Amor, 2009) in the normal appearing tissue, in which sub-pathological changes have been shown to be present (Filippi et al, 1998; Graumann et al, 2003; Lindberg et al, 2004; Zeis et al, 2008) Some of these areas of microglial activation are suggested to transform into full, active demyelinating lesions characterized by massive infiltration of immune cells, primarily of the monocyte/macrophage lineage

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