MicroRNAs are short (21-25 nucleotides) non-coding RNA molecules that regulate gene expression by activating or repressing mRNA transcription. About 2000 have been identified thus far (Kozomara et al. Nucleic Acids Res 2019;47:155-162), and many have potential utility as biomarkers in the diagnosis, monitoring and treatment of multiple sclerosis.
One of the most studied is miRNA-155 (formerly B cell integration cluster, BIC), which is highly expressed in B and T cells. It is involved in fine-tuning the expression of B cells and T cells (CD8+, CD4+, Tregs) that determines the balance between tolerance and autoimmunity (Seddiki et al. Immunology 2014;142:32-38). In the CNS, miR-155 enhances astrocyte activation and shifts microglia to a pro-inflammatory phenotype (Gaudet et al. Neuroscientist 2018;24:221-245).
Diagnosis: miRNA-155 expression in peripheral blood mononuclear cells (PBMC) was reportedly three-fold higher in MS patients compared to healthy controls, suggesting a possible role in diagnosis (Paraboschi et al. Int J Mol Sci 2011;12:8695-8712). More recently, miRNA-155 expression in CSF was also shown to be useful in discriminating MS from healthy controls (Shademan et al. Clin Neurol Neurosurg 2023;232:107873).
Disease severity: One study found that miRNA-155 regulates the expression of MS risk genes (PIK3CA, PIK3R1, PIK3R2), indicating that it may be a useful marker of disease severity (Luo et al. Mult Scler Relat Disord 2020;41:102044). To date, several disease mechanisms contributing to disease severity have been implicated.
In an EAE model, miRNA-155 promoted the differentiation of pro-inflammatory Th1 and Th17 cells (Zhang et al. J Neuroimmunol 2014;266:56-63). In human endothelial cell cultures, the effects of miRNA-155 on junction proteins and adhesion molecules contributed to increased blood-brain barrier permeability (Lopez-Ramirez et al. FASEB J 2014;28:2551-2565). Within the CNS, miRNA-155 was shown to be upregulated in MS lesions, where it promoted phagocytosis by macrophages and increased demyelination (Junker et al. Brain 2009;132(Pt 12):3342-3352).
Treatment response: A study of glatiramer acetate found overexpression of four miRNAs in untreated MS patients compared to healthy controls (Waschbisch et al. PLoS One 2011;6:e24604). miRNA-155 levels were unchanged following treatment with glatiramer acetate or interferon-beta, although levels of two other miRNAs (miR-146a, miR-142-3p) appeared to be normalized.
In contrast, miRNA-155 levels were reduced in RRMS patients during and following a six-month course of natalizumab (Mameli et al. PLoS One 2016;11:1-11). An in vitro study found that natalizumab, fingolimod and dimethyl fumarate reduced miRNA-155 expression in monocytes derived from MS patients (Michell-Robinson et al. Ann Clin Transl Neurol 2016;3:27–41). Similarly, DMF reduced miRNA-155 expression in astrocyte cultures derived from murine and human brain cells (Galloway et al. Ann Clin Transl Neurol 2017;4:381-391). However, a separate Italian study reported that miRNA-155 levels were not elevated in MS patients and were not reduced during treatment with DMF (Giuliani et al. Mult Scler Relat Disord 2021;54:103126).
While miRNAs are promising biomarkers, there is a need to standardize sample collection (plasma, CSF, PBMCs) and analytic methods, and to determine environmental and disease-related factors that may influence miRNA expression in MS patients throughout the disease course.