Multiple sclerosis: Mechanisms of myelin phagocytosis and lesion expansion

Multiple sclerosis (MS) is characterized by immune activation and focal demyelination in the central nervous system. The aim of this thesis was to gain more insight into the mechanisms of myelin phagocytosis by resident microglia and infiltrating macrophages. We first evaluated the expression of the most frequently used histological microglia markers (HLA-DR, CD68 ad Iba1) in different activation stadia of microglia. We found a similar, yet not identical, overall expression pattern and concluded that these markers have different potential for neuropathological analysis. Next, we set up a hypothesis-free microarray approach to evaluate the microenvironment throughout MS lesion progression, and to identify genes that could potentially be involved in MS lesion onset or progression, or lesion halt. We identified several genes of interest: CHIT1, GPNMB, CCL18, OLR1, CD68, MSR1, CXCL16, CXCR4, NPY, KANK4, NCAN, TKTL1, and ANO4. Since scavenger receptors (SRs) have been indicated to play a role in demyelination, we also specifically studied their mRNA and protein expression in different MS lesions. We found OLR1, CD68, MSR1, and CXCL16 upregulated in and around chronic active MS lesions. Furthermore, in vitro downregulation of the SRs MSR1 and CXCL16 reduced myelin uptake, indicating a role for SRs in demyelination in MS. Last, we compared the uptake of myelin isolated from MS patients and healthy controls, as changes in MS myelin might also contribute to the onset of demyelination in MS. Indeed, MS myelin was phagocytosed more efficiently than control myelin by the human macrophage cell line THP-1 and by primary human microglia