MicroRNA-148a facilitates inflammatory dendritic cell differentiation and autoimmunity by targeting MAFB
MicroRNA-148a facilitates inflammatory dendritic cell differentiation and autoimmunity by targeting MAFB
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MicroRNA-148a 通过靶向 MAFB 促进炎症树突状细胞分化和自身免疫
DOI：
10.1172/jci.insight.133721
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发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Shen Nan
中科院分区：
文献类型：
--
作者：
Meng Yao;Li Jun;Ye Zhizhong;Yin Zhihua;Sun Qing;Liao Zhuojun;Li Guanhua;Deng Jun;Liu Lu;Yu Yuqing;Wu Li;Zhou Haibo;Shen Nan
单核细胞衍生的 DC (moDC) 与自身免疫的发病机制有关，但决定这些细胞分化潜力的分子途径仍不清楚。在这里，我们报告 microRNA-148a (miR-148a) 是 moDC 分化的关键调节因子。首先，miR-148a 缺陷损害了 moDC 的体外和体内发育。一项机制研究表明，MAFB（一种阻碍 moDC 分化的转录因子）是 miR-148a 的直接靶标。此外，一项启动子研究发现 miR-148a 可以被 PU.1 转录诱导，这对于 moDC 的生成至关重要。 miR-148a 消除消除了 PU.1 对 MAFB 的抑制。此外，我们发现银屑病患者的单核细胞中 miR-148a 增加，并且 miR-148a 缺乏或皮内注射 antagomir-148a 极大地减轻了银屑病样小鼠模型中银屑病样症状的发展。因此，这些结果确定了 PU.1-miR-148a-MAFB 电路在 moDC 分化中的关键作用，并提出了自身免疫的潜在治疗途径。
Monocyte-derived DCs (moDCs) have been implicated in the pathogenesis of autoimmunity, but the molecular pathways determining the differentiation potential of these cells remain unclear. Here, we report that microRNA-148a (miR-148a) serves as a critical regulator for moDC differentiation. First, miR-148a deficiency impaired the moDC development in vitro and in vivo. A mechanism study showed that MAFB, a transcription factor that hampers moDC differentiation, was a direct target of miR-148a. In addition, a promoter study identified that miR-148a could be transcriptionally induced by PU.1, which is crucial for moDC generation. miR-148a ablation eliminated the inhibition of PU.1 on MAFB. Furthermore, we found that miR-148a increased in monocytes from patients with psoriasis, and miR-148a deficiency or intradermal injection of antagomir-148a immensely alleviated the development of psoriasis-like symptoms in a psoriasis-like mouse model. Therefore, these results identify a pivotal role for the PU.1-miR-148a-MAFB circuit in moDC differentiation and suggest a potential therapeutic avenue for autoimmunity.