CSF microRNAs discriminate MS activity and share similarity to other neuroinflammatory disorders

OBJECTIVE: To perform a comprehensive multicompartment analysis of microRNA (miRNA) expression in multiple sclerosis (MS) linked to disease activity and compared with other neuroinflammatory diseases through a retrospective cross-sectional study. METHODS: One hundred twenty-seven miRNAs were measured by PCR arrays on pooled CSF, serum, and peripheral blood mononuclear cell (PBMC) samples of 10 patients with relapsing MS and 10 controls. Sixty-four miRNAs were then measured by quantitative PCR on individual CSF samples of patients with relapsing or remitting MS and controls (n = 68). Fifty-seven miRNAs were analyzed in the CSF from a second cohort (n = 75), including patients with MS, neuroinfectious, or neuroinflammatory diseases and controls. MiRNAs significantly dysregulated in the CSF were analyzed on individual serum/PBMC samples (n = 59/48) of patients with relapsing or remitting MS and controls. Post hoc analysis consisted of principal component analysis (PCA), gene set, and pathway enrichment analysis. RESULTS: Twenty-one miRNAs were differentially expressed, mainly upregulated in the CSF during MS relapses. Relapsing MS and neuroinfectious/inflammatory diseases exhibited a partially overlapping CSF miRNA expression profile. Besides confirming the association of miR-146a-5p/150-5p/155-5p with MS, 7 miRNAs uncharacterized for MS emerged (miR-15a-3p/124-5p/149-3p/29c-3p/33a-3p/34c-5p/297). PCA showed that distinct miRNA sets segregated MS from controls and relapse from remission. In silico analysis predicted the involvement of these miRNAs in cell cycle, immunoregulation, and neurogenesis, but also revealed that the signaling pathway pattern of remitting MS is more akin to controls rather than patients with relapsing MS. CONCLUSIONS: This study highlights the CSF-predominant dysregulation of miRNAs in MS by identifying a signature of disease activity and intrathecal inflammation among neuroinflammatory disorders.