RT Journal Article
SR Electronic
T1 Disulfiram and Diphenhydramine Hydrochloride Upregulate miR-30a to Suppress IL-17-Associated Autoimmune Inflammation
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9253
OP 9266
DO 10.1523/JNEUROSCI.4587-15.2016
VO 36
IS 35
A1 Ming Zhao
A1 Dingya Sun
A1 Yangtai Guan
A1 Zhihong Wang
A1 Daoqian Sang
A1 Mingdong Liu
A1 Yingyan Pu
A1 Xue Fang
A1 Dan Wang
A1 Aijun Huang
A1 Xiaoying Bi
A1 Li Cao
A1 Cheng He
YR 2016
UL http://www.jneurosci.org/content/36/35/9253.abstract
AB T-helper 17 (Th17) cells play an important role in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease that affects the CNS. In the present study, MicroRNA sequencing (miRNA-seq) was performed in mouse Th0 and Th17 cells to determine the critical miRNAs that are related to Th17 differentiation. We found that miR-30a was significantly downregulated during mouse Th17 differentiation. In addition, the level of miR-30a in CD4+ T cells from peripheral blood of MS patients and experimental autoimmune encephalomyelitis (EAE) animal models was also decreased and inversely correlated with the expression of interleukin 17a, the canonical cytokine of Th17 cells. Moreover, overexpression of miR-30a inhibited Th17 differentiation and prevented the full development of EAE, whereas interference of miR-30a promoted Th17 differentiation. Mechanism studies showed that miR-30a reduced IRF4 expression by specifically binding with the 3′-untranslated region. Through screening of 640 different Food and Drug Administration (FDA)-approved drugs, we found that disulfiram and diphenhydramine hydrochloride were effective candidates for inhibiting Th17 differentiation and ameliorating EAE development through upregulating miR-30a. To our knowledge, the present work is not only the first miRNA-seq study focusing on Th17 differentiation, but also the first chemical screening for FDA-approved drugs that inhibit Th17 differentiation through regulating miRNA expression.SIGNIFICANCE STATEMENT The present work is the first miRNA sequencing (miRNA-seq) study focusing on T-helper 17 (Th17) differentiation. By miRNA deep sequencing, we found that miR-30a was downregulated during Th17 differentiation. miR-30a was also decreased in CD4+ T cells from multiple sclerosis patients and experimental autoimmune encephalomyelitis (EAE) mice. miR-30a reduced IRF4 expression by specific binding with the 3′-untranslated region and thus suppressed Th17 differentiation and prevented the full development of EAE. Interestingly, by performing a chemical screen with Food and Drug Administration-approved small-molecule drugs, we found that disulfiram and diphenhydramine upregulated miR-30a and suppressed Th17-associated autoimmune demyelination.