Is It worth Considering Circulating microRNAs in Multiple Sclerosis?

Abstract

New evidence has highlighted that miRNA production and trafficking can be dysregulated in both autoimmmune and neurological disorders. Multiple sclerosis (MS) in particular is an autoimmune pathology leading to neurodegeneration. Profiling studies performed on cells derived from MS patients have described a dysregulated network of miRNAs in both immune and neural cells. Interestingly, new evidence has emerged showing that circulating miRNAs are also dysregulated in MS body fluids, including plasma/serum and cerebrospinal fluid. This review summarizes the current scientific theories on the function of this altered circulating miRNA network. It builds up new insights about miRNA transfer mechanisms including extracellular vesicle trafficking involved in cell-to-cell communication and the possible physiopathological functions of these transfers in MS. Finally, this review proposes that monitoring altered miRNA expression levels could serve as a potential biomarker read-out of MS subtype and severity.

Keywords: biomarkers; circulating miRNAs; demyelination; exosomes; extracellular vesicles; inflammation; multiple sclerosis; relapses.

Figures

Figure 1

Overlapping between dysregulated miRNAs in plasma and lymphocytes or in plasma and the CNS of MS patients. Dysregulated miRNAs from plasma and lymphocytes (left panel) or from plasma and the CNS (right panel) were either identical (overlapping area) or not (single area). Data were compiled from miRNA profiling studies performed on plasma (, –11, 18), immune cells [B (–22) or T cells (, –26)], and the CNS (astrocytes, oligodendrocytes, brain endothelial cells, whole brain lesions, and whole brain) (, –30). Briefly, we selected dysregulated miRNAs from microarray profiling studies, filtered out miRNAs with non-significant variation of the expression level, and highlighted commonly dysregulated miRNAs. All overlapping miRNAs are listed and those written in white color are dysregulated in at least three compartments, including plasma and the CNS; miR, miRNA.

Figure 2

Major pathways for extracellular vesicle biogenesis and for miRNA incorporation into exosomes. (1) The exosomal pathway includes MVB formation, exosome budding into MVB lumen, and exocytosis-mediated exosomal release. (a) Ubiquitinated RISC- and ESCRT-dependent incorporation of miRNAs into exosomes: model from Gibbings and colleagues (35). (b) Main pathway of miRNA biogenesis detailed in the Section “Introduction.” (2) The microvesicular pathway: miRNA uptake by microvesicles remains to be clarified. (3) The apoptotic pathway: apoptotic cells release apoptotic bodies containing fragment of the nucleus and putative miRNAs.

Figure 3

Functions of dysregulated cellular and circulating miRNAs in MS/EAE physiopathology. Myelin-derived peptides reach the lymph node as free autoimmune-prone antigens or associated with antigen-presenting cells. It results in B cell and T cell activation and migration of these cells across a porous brain blood barrier. Unbalanced differentiation toward proinflammatory T cell subsets Th1 and Th17 is amplified by cellular miR-155 and miR-326 upregulation and by cell non-autonomous transfer of these miRNAs between T cells through putative EVs. In the CNS, miR-155 participates to microglia-mediated inflammation/neurodegeneration. Brain inflammation is also aggravated by miR-155-mediated decrease of CD47, driving vulnerability of neural cells (evidence being for astrocytes) toward microglia-mediated phagocytosis. miRNAs are depicted as red dashes. EVs appear in the color of the producing cell and contain a single effective miRNA for simplification. HEV, high endothelial venules.

Figure 4

Model of the cell non-autonomous effect of circulating miRNAs. Exacerbated T cell differentiation (evidence being mainly for Th17 cells) might be a feature of the transition from remission to relapses (3). The initial state (remission) would depict poorly differentiated T cells, whereas it ends up during relapses with exaggerated T cell differentiation and activation. The transition from remission to relapses also correlates with increased dysregulation of miRNAs (3, 5) that would drive inflammatory T cell differentiation and activation. The model of cell non-autonomous effects of miRNAs consists in the transfer through EVs of T cell differentiation-driving miRNAs. The cause of initial miRNA dysregulation remains unknown. Light blue, dark blue, and yellow cells depict Th1, Th17, and non-differentiated Th0 cells, respectively.