MiR-125a-5p Regulates Vitamin D Receptor Expression in a Mouse Model of Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis (MS) is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system. Although the symptoms of MS can be managed by vitamin D3 treatment alone, this condition cannot be completely eradicated. Thus, there might be unknown factors capable of regulating the vitamin D receptor (VDR). Genome-wide analysis showed that miRNAs were associated with VDRs. We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS, mice with experimental autoimmune encephalomyelitis (EAE), which was induced by myelin oligodendrocyte glycoprotein 35-55 peptides. EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice. And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice. In addition, VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice. Importantly, activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice. Interestingly, VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn. More importantly, inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice. These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.

Long non-coding RNA ANRIL knockdown suppresses apoptosis and pro-inflammatory cytokines while enhancing neurite outgrowth via binding microRNA-125a in a cellular model of Alzheimer's disease

“…In addition, miR-125a negativity modulated the levels of the pro-inflammatory chemokine expressed and secreted by normal T cell, by targeting Krüppel-like factor 13 in T cells separated from patients with Sle (30). Furthermore, mir-125a could activate vitamin d receptors in a mouse model of experimental autoimmune encephalomyelitis, which may enhance the treatment effect of vitamin d in multiple sclerosis; miR-125a and vitamin D receptor are both located at the same neurons of the ventral horn (31). However, mir-125a appears to act as a pro-inflammatory factor as well.…”

Circulating microRNA Expression Profiling Identifies miR-125a-5p Promoting T Helper 1 Cells Response in the Pathogenesis of Hashimoto's Thyroiditis

“…Among them, 22 miRNAs showed significantly dysregulated expression in HT patients. Some of these dysregulated miRNAs, including miR-132, miR-301a and miR-125a (overexpressed) (17)(18)(19) and miR-33a, miR-196b, and miR-146b (downregulated) (8,20,21), have been reported to be involved in immunological pathways or related to various autoimmune diseases. However, the relationships between these miRNAs and HT have rarely been reported.…”

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

“…MiR-223—which also has a role in microglia and macrophages in remyelination—and miR-27a are upregulated in retinal ganglion cells in EAE following local damage, and are associated with neuroprotection from glutamate toxicity [ 61 ]. In the spinal ventral horn during EAE, Vitamin D Receptor (VDR) expression on neurons is reduced, while miR-125a is upregulated, and both activation of the VDR and inhibition of miR-125a are associated with reduced clinical scores, suggesting a neuroprotective role [ 59 ]. In the cuprizone model, miR-155 and miR-20a upregulation during demyelination may also be important for neuronal survival and remyelination by inducing the Nogo Receptor via suppression of mothers against decapentaplegic homolog 2 (SMAD2) and SMAD4.…”