Disulfiram and Diphenhydramine Hydrochloride Upregulate miR-30a to Suppress IL-17-Associated Autoimmune Inflammation
Disulfiram and Diphenhydramine Hydrochloride Upregulate miR-30a to Suppress IL-17-Associated Autoimmune Inflammation
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双硫仑和盐酸苯海拉明上调 miR-30a 以抑制 IL-17 相关的自身免疫炎症
DOI：
10.1523/jneurosci.4587-15.2016
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发表时间：
2016
影响因子：
5.3
通讯作者：
He Cheng
中科院分区：
文献类型：
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作者：
Zhao Ming;Sun Dingya;Guan Yangtai;Wang Zhihong;Sang Daoqian;Liu Mingdong;Pu Yingyan;Fang Xue;Wang Dan;Huang Aijun;Bi Xiaoying;Cao Li;He Cheng
t -辅助性17 （Th17）细胞在多发性硬化症（MS）的发病机制中起重要作用，多发性硬化症是一种影响中枢神经系统的自身免疫性脱髓鞘疾病。在本研究中，我们对小鼠Th0和Th17细胞进行了MicroRNA测序（miRNA-seq），以确定与Th17分化相关的关键mirna。我们发现miR-30a在小鼠Th17分化过程中显著下调。此外，MS患者和实验性自身免疫性脑脊髓炎（EAE）动物模型外周血CD4+ T细胞中miR-30a水平也下降，并与Th17细胞的典型细胞因子白介素17a的表达呈负相关。此外，过表达miR-30a抑制了Th17的分化，阻碍了EAE的充分发展，而干扰miR-30a促进了Th17的分化。机制研究表明，miR-30a通过特异性结合3 ' -非翻译区降低IRF4的表达。通过筛选640种不同的FDA批准药物，我们发现双硫仑和盐酸苯海拉明是通过上调miR-30a抑制Th17分化和改善EAE发展的有效候选药物。据我们所知，本工作不仅是第一个关注Th17分化的miRNA-seq研究，也是第一个通过调节miRNA表达抑制Th17分化的fda批准药物的化学筛选。本工作是第一个专注于t -辅助性17 （Th17）分化的miRNA测序（miRNA-seq）研究。通过miRNA深度测序，我们发现miR-30a在Th17分化过程中下调。多发性硬化症患者和实验性自身免疫性脑脊髓炎（EAE）小鼠的CD4+ T细胞中miR-30a也降低。miR-30a通过特异性结合3 ' -非翻译区降低IRF4表达，从而抑制Th17分化，阻止EAE的充分发展。有趣的是，通过使用美国食品和药物管理局批准的小分子药物进行化学筛选，我们发现双硫仑和苯海拉明上调miR-30a并抑制th17相关的自身免疫性脱髓鞘。
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.