Gene Expression Profiling of Multiple Sclerosis Pathology Identifies Early Patterns of Demyelination Surrounding Chronic Active Lesions

Abstract

In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1, and ANO4. Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16, and OLR1, and lipid uptake, such as CHIT1, GPNMB, and CCL18. Except CCL18, these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.

The role of chemokines and chemokine receptors in multiple sclerosis

“…CCL18 was identified as one of the top 3 up-regulated genes on the verge of chronic active MS lesions, where there is a large amount of foam and microglia/macrophages that accumulate myelin. This is consistent with previous research by Boven LA et al [41,112]. CCL18 recruits a subset of human regulatory T cells and inhibits the proliferation of effector T cells through the IL-10 production in vitro.…”

“…CCL18 recruits a subset of human regulatory T cells and inhibits the proliferation of effector T cells through the IL-10 production in vitro. CCL18 expressed by macrophages also ingests myelin, producing an immunosuppressive phenotype [41]. Incubation of microglia with dexamethasone resulted in a significant upregulation of CCL18 [74].…”

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

“…(B) Microglial marker RNA expression in active and inactive chronic lesions. Probability values are derived from nonparametric Kruskal–Wallis test with Dunn post hoc test on publicly available data deposited in the Gene Expression Omnibus database originating from Hendrickx et al CHIT1 = chitotriosidase; CHI3L1 = chitinase‐3–like protein 1; CON GM = gray matter control; CON WM = white matter control; MS GM = gray matter from MS patients; MS WM = white matter lesions from MS patients; MS PL CA = perilesion of chronic active lesions from MS patients; MS PL CI = perilesion of chronic inactive lesions from MS patients; MS RIM CA = rim of chronic active lesions from MS patients; MS RIM CI = rim of chronic inactive lesions from MS patients; TREM2 = triggering receptor expressed on myeloid cells 2.…”

“…The dataset of Hendrickx et al subsequently provided more detail on lesions and allowed us to distinguish between the rim and perilesion region around chronic active and inactive lesions. As originally reported, CHIT1 is upregulated 10.2‐fold in the rim of chronic active lesions versus the rim of chronic inactive lesions.…”

“…3 Neurofilament light chain (NfL), a structural axonal component released upon injury, is one of the most studied biomarkers for followup of disease activity and treatment response in MS. 4 Evidence for a role of innate immune cells such as the CNS-resident macrophages or microglia in MS pathogenesis is growing, and the heterogeneity of microglial subsets is increasingly recognized. [5][6][7][8] Hence, we investigate 3 main macrophage and microglia-related markers in CSF as potential biomarkers: chitotriosidase (also known as chitinase 1 [CHIT1]), chitinase-3-like protein 1 (CHI3L1, also known as YKL- 40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Both CHIT1 and CHI3L1 are secreted by activated macrophages and are markers of microglial activation.…”