miR-145 and miR20a-5p Potentially Mediate Pleiotropic Effects of Interferon-Beta Through Mitogen-Activated Protein Kinase Signaling Pathway in Multiple Sclerosis Patients

Abstract

MicroRNAs (miRNAs) are crucial to the immunopathogenesis of multiple sclerosis (MS). The mechanism of action of interferon beta (IFN-β) in relapsing-remitting (RR) MS patients is largely unknown. miR-145 and miR-20a-5p previously reported as diagnosis biomarker in treatment naïve RRMS patients and their expression after IFN-β therapy might be indicative of molecular mechanism of IFN-β. Cross-talking between JAK/STAT pathway and complementary pathways like MAPK is important in IFN-β signaling. Here, in order to clarify the ambiguous molecular mechanism of IFN-β and evaluate the potential use of them as a biomarker for monitoring of therapy, we investigated the expression of miR-145 and miR-20a-5p in blood sample of 15 treatment naïve RRMS patients, 15 IFN-β-treated RRMS patients, and 15 healthy volunteers (HVs). In silico molecular signaling pathway enrichment analysis was fulfilled on validated and predicted targets of miR-145 and miR-20a-5p to probe the plausible role of them on molecular effects of IFN-β. We identified miR-145 and miR-20a-5p level was normalized in IFN-β-treated patients, and MAPK pathway was one of the most relevant pathways that recognized by molecular signaling pathway enrichment analysis. Moreover, ROC curve analysis of miR-145 indicated that this miRNA could be used for monitoring of response to IFN-β therapy. Restoration of miR-145 and miR-20a expression in IFN-β-treated patients suggests that pleiotropic effects of IFN-β might be through miRNAs. Enrichment of MAPK pathway underscores the importance of non-canonical pathways in IFN-β signaling.

Retracted: miR‐145 eliminates lipopolysaccharides‐induced inflammatory injury in human fibroblast‐like synoviocyte MH7A cells

“…[29][30][31][32] LPS increases the secretion of pro-inflammatory cytokines in fibroblast-like synoviocytes, which leads to the activation of the PI3K/ AKT and MAPK/mTOR pathways, thereby inducing apoptotic and inflammatory injury in these cells. [34][35][36][37] We demonstrated that miR-145 could partially eliminate the LPS-induced activation of PI3K/AKT and MAPK/ mTOR pathways in MH7A cells, implying that the protective activities of miR-145 might be realized by blocking the PI3K/AKT and MAPK/mTOR pathways. Protein expressions of core components of (A), PI3K/AKT, and (B), MAPK pathways were evaluated, after MH7A cells were transfected with miR-145 mimic or mimic-control, and subsequently treated with 5 μg/mL of LPS for 5 hours.…”

“…LPS, lipopolysaccharides miR-145 to apoptosis and inflammation is its capacity to block the PI3K/AKT and MAPK/mTOR pathways. [34][35][36][37] We demonstrated that miR-145 could partially eliminate the LPS-induced activation of PI3K/AKT and MAPK/ mTOR pathways in MH7A cells, implying that the protective activities of miR-145 might be realized by blocking the PI3K/AKT and MAPK/mTOR pathways. We additionally found that miR-145 could block PI3K/AKT and mTOR pathways in the LPS-untreated MH7A cells, but the blockage failed to modulate cell apoptosis and inflammation.…”

MicroRNA-20a-5p suppresses IL-17 production by targeting OSM and CCL1 in patients with Vogt-Koyanagi-Harada disease

“…We also showed that miR-20a-5p suppressed the production of the proinflammatory cytokine IL-17 but did not alter production of IFN-γ, suggesting that a low miR-20a-5p is associated with an enhanced inflammatory response. A downregulation of miR-20a-5p has also been reported earlier in several autoimmune diseases17 and human cancer26 but has not yet been investigated during intraocular inflammation.…”

“…There was a report showed that miR-20a-5p could be used as biomarker in the treatment response of naive patients with relapsing remitting MS with interferon-β (IFN-β) 17. These findings also suggested that miR-20a-5p might be an important player in the pathophysiology of MS 18.…”

Environmental Influencers, MicroRNA, and Multiple Sclerosis

“…108,110,116,121,130,145,235 Likewise, Ehtesham et al demonstrated that IFN-β can restore the expression levels of the previously described MS-or EAE-associated miRNAs: miR-145 and miR-20a (Tables 2 and 5). 24,122,138,171,234,241,260 Similarly, Manna et al studied 16 differentially expressed miRNAs in IFN-β treated RRMS patients vs naive patients. Of these 16 miRNAs, 2 (miR-22-3p and miR-660-5p) were upregulated and 14 (miR-486-5p, miR-451a, miR-let-7b-5p, miR-320b, miR-122-5p, miR-215-5p, miR-320d, miR-19b-3p, miR-26a-5p, miR-142-3p, miR-146a-5p, miR-15b-3p, miR-23a-3p, and miR-223-3p) were downregulated ( Table 5).…”