Natalizumab Therapy Modulates miR-155, miR-26a and Proinflammatory Cytokine Expression in MS Patients

Abstract

MicroRNAs fine-tune the regulation of Th1/Th17 lymphocyte subsets in multiple sclerosis. We investigated the expression of miRNAs (previously associated with mycobacterial and viral infections) in MS patients and healthy donors (HD) following 6 months natalizumab therapy. In addition, Th1/Th17 cytokines and the presence of anti-EBNA1/VCA IgG in MS patients with different pattern of miRNA expression have been evaluated. MiR-155, miR-26a, miR-132, miR-146a and Th1/Th17 cytokines expression was detected by RT-real time PCR; moreover anti-EBNA1 and VCA IgG titres were measured by ELISA. We observed an up-regulation of miR-155 (p value = 0.009) and miR-132 (p value = 0.04) in MS patients compared to HD. In MS patients, IL-17a (p = 0.037), IFN γ (p = 0.012) and TNFα (p = 0.015) but not IL-6 were over-expressed compared to HD. Two different miRNAs patterns associated to the expression of different cytokines were observed in the MS cohort. Moreover, a down-regulation of miR-155 and miR-26a was seen in MS patients during and after natalizumab therapy. MS patients that over-expressed miR-155 showed a higher EBNA1 IgG titer than MS patients with high levels of miR-26a. In conclusions the expression of particular miRNAs modulates the pro-inflammatory cytokine expression and the humoral response against EBV and this expression is natalizumab regulated.

Emerging Approaches for Validating and Managing Multiple Sclerosis Relapse

“…Thus, assaying miRNAs from PBMCs and sera indicate not only the overall inflammatory state but also specify whether the immune system is acting in a beneficial or pathogenic manner. miR-155, which promotes pathogenic helper T cell and pro-inflammatory myeloid cell activation, is elevated during relapse and responds to disease-modifying therapy (DMT) (28). …”

Environmental Influencers, MicroRNA, and Multiple Sclerosis

“…[160][161][162][163]166 Current therapeutic approaches exert a notable impact on some of the miRNAs associated with MS. FDA-approved drugs have shown their efficiency in regulating some of the known MS-associated miRNAs, namely, miR-146a, miR-155, miR-145, miR-20a, miR-22, miR-320b, miR-146a, miR-23a, miR-223, miR-BART3-5p, and EBV-miR-BART11 -5p. 132,145,[170][171][172]175,177,178,259 However, in the future, novel approaches need to focus on designing drugs that modulate the miRNA networks as a target. This approach may need more time, expense, and research, but could provide a better life for these patients.…”

“…138 Besides, Mameli et al reported that natalizumab could downregulate miR-155 and miR-26a, miRNAs that had previously proven to increase MS pathogenicity (Tables 2 and 5). 130,145,177 Dimethyl fumarate (DMF), another FDA-approved MS treatment drug, has similarly shown efficacy in reducing the expression of the pathogenic miR-155 ( Table 5). 178 Fingolimod (FGM), also FDA-approved MS drug, proved to significantly reverse the aberrant miR-15b, miR-23a, and miR-223 expression after 6 months of the administration.…”

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

“…In addition, in the animal model of MS (experimental autoimmune encephalomyelitis, EAE), genetic deletion of the miRNA cluster miR-106a∼363 (containing Natalizumab-regulated miR-20b) resulted in a more severe disease course, and it upregulated in vivo the miR-20b target genes [89]. In addition, the treatment with Natalizumab restored the expression levels of miR-26a and miR-155 [90], which were upregulated in PBMCs of MS patients, as well as in urine exosome, plasma, and in the spinal cord samples from EAE mice [82]. Notably, miR-155 plays a central role in many processes involved in the pathogenesis of MS, such as immune cell activation, neurodegeneration and permeabilization of the BBB [18].…”