Role of miR-9-5p in preventing peripheral neuropathy in patients with rheumatoid arthritis by targeting REST/miR-132 pathway
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MicroRNAs (miRNAs) are found to play a key role in neural cell differentiation, peripheral nerve injury, and rheumatoid arthritis (RA). However, no study has yet been conducted highlighting their role in RA-induced peripheral neuropathy. Here, we investigated the role of miRNAs in RA-induced peripheral neuropathy. Levels of six miRNAs were detected in serum collected from 15 patients with RA and peripheral neuropathy and 16 patients with RA. In vitro, Schwann cells were treated with 0.1 ng/mL IL-6 and 20 ng/mL TNF-α. The expression level of miR-9-5p and its association with the repressor element-1 silencing transcription factor (REST) were investigated. The roles of miR-9-5p and REST in Schwann cell injury were examined after transfection of miR-9-5p mimics or REST siRNA. In patients with RA and peripheral neuropathy, serum miR-9-5p was significantly downregulated when compared with RA. In IL-6- and TNF-α-stimulated Schwann cells, apoptosis was induced, while the cell viability and level of miR-9-5p were inhibited. A significantly negative correlation was observed between miR-9-5p and REST. Transfection of miR-9-5p mimics and REST siRNA significantly reversed the inhibition of cell viability and induction of apoptosis caused by IL-6 and TNF-α. In addition, overexpression of miR-9-5p upregulated the expression of miR-132, miRNA targeting E1A binding protein EP300 (EEP300), phosphatase and tensin homolog (PTEN) and forkhead box O3 (FOXO3). These results showed that Schwann cells were protected by miR-9-5p from inflammatory damage by targeting REST/miR-132 pathway, which could provide new targets for treatment of RA-induced peripheral neuropathy.
KeywordsmicroRNA Peripheral neuropathy Rheumatoid arthritis Schwann cell
ZZ. L. and XF. L. designed the study. ZZ. L., YS. L., and QH. L. performed experiments and collected data. ZZ. L., ZC. Z., and L. J. analyzed and interpreted the data. ZZ. L. and XF. L. wrote the manuscript. All authors have read and approved the final version of this manuscript.
This work was financially supported by the Linyi Medical Science Development Plan (201515002).
Compliance with ethical standards
All protocols were approved by the Human Ethics Committee of Qilu Hospital of Shandong University.
Conflict of interest
The authors declare that they have no conflict of interest.
- Aggarwal D, Singla S (2017) Prevalence of autonomic neuropathy in patients of rheumatoid arthritis and its correlation with disease severity. J Clin Diagn Res 11:Oc09–oc13Google Scholar
- Bitel CL, Perrone-Bizzozero NI, Frederikse PH (2010) HuB/C/D, nPTB, REST4, and miR-124 regulators of neuronal cell identity are also utilized in the lens. Mol Vis 16:2301–2316Google Scholar
- Bruchfeld A, Goldstein RS, Chavan S, Patel NB, Rosas-Ballina M, Kohn N, Qureshi AR, Tracey KJ (2010) Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis. J Intern Med 268:94–101Google Scholar
- Chen JQ, Papp G, Szodoray P, Zeher M (2016) The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev 15:1171–1180Google Scholar
- de la Rica L, Garcia-Gomez A, Comet NR, Rodriguez-Ubreva J, Ciudad L, Vento-Tormo R, Company C, Alvarez-Errico D, Garcia M, Gomez-Vaquero C et al (2015) NF-kappaB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation. Genome Biol 16:2CrossRefGoogle Scholar
- Lubrano E, Mesina F, Caporali R (2018) Clinical remission in rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol 36:900–910Google Scholar
- Nadkar MY, Agarwal R, Samant RS, Chhugani SJ, Idgunji SS, Iyer S, Borges NE (2001) Neuropathy in rheumatoid arthritis. J Assoc Physicians India 49:217–220Google Scholar
- Qin W, Zhao W, Ho L, Wang J, Walsh K, Gandy S, Pasinetti GM (2010) Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer’s disease-type amyloid neuropathology and spatial memory deterioration. Ann N Y Acad Sci 1147:335–347CrossRefGoogle Scholar
- Wang W, Zhang Y, Zhu B, Duan T, Q X, Wang R, L L, Jiao Z (2015) Plasma microRNA expression profiles in Chinese patients with rheumatoid arthritis. Oncotarget 6:42557–42568Google Scholar
- Zhu L, Hao J, Cheng M, Zhang C, Huo C, Liu Y, Du W, Zhang X (2018) Hyperglycemia-induced Bcl-2/Bax-mediated apoptosis of Schwann cells via mTORC1/S6K1 inhibition in diabetic peripheral neuropathy. Exp Cell Res 367:186–195Google Scholar