microRNA-146a promotes mycobacterial survival in macrophages through suppressing nitric oxide production.
microRNA-146a promotes mycobacterial survival in macrophages through suppressing nitric oxide production.
复制标题
microRNA-146a 通过抑制一氧化氮的产生来促进巨噬细胞中分枝杆菌的存活。
DOI：
10.1038/srep23351
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发表时间：
2016-03-30
影响因子：
4.6
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Li M;Wang J;Fang Y;Gong S;Li M;Wu M;Lai X;Zeng G;Wang Y;Yang K;Huang X
巨噬细胞在宿主先天性抗分枝杆菌防御中起着至关重要的作用，这受到包括microRNA在内的多种因素的严格调控。我们先前的研究表明，一组microRNA在分枝杆菌感染后在巨噬细胞中显著上调。在此，我们研究了miR-146 a在分枝杆菌感染过程中的生物学功能。在体外和体内，牛分枝杆菌BCG感染后均可诱导miR-146 a表达。诱导型miR-146 a可以抑制诱导型一氧化氮合酶（iNOS）的表达和NO的产生，从而促进分枝杆菌在巨噬细胞中的存活。内源性miR-146 a的抑制增加了NO的产生和分枝杆菌的清除。此外，miR-146 a在BCG感染期间减弱了核因子κB和丝裂原活化蛋白激酶信号通路的激活，这反过来抑制了iNOS表达。在机制上，miR-146 a在转录后水平直接靶向肿瘤坏死因子（TNF）受体相关因子6（TRAF 6）。沉默TRAF 6降低BCG感染的巨噬细胞中iNOS的表达和NO的产生，而过表达TRAF 6逆转了miR-146 a介导的对NO产生和分枝杆菌清除的抑制。因此，我们证明了miR-146 a通过靶向TRAF 6抑制NO产生来调节宿主对分枝杆菌感染的防御的新作用，这可能为结核病提供有希望的治疗靶点。
Macrophages play a crucial role in host innate anti-mycobacterial defense, which is tightly regulated by multiple factors, including microRNAs. Our previous study showed that a panel of microRNAs was markedly up-regulated in macrophages upon mycobacterial infection. Here, we investigated the biological function of miR-146a during mycobacterial infection. miR-146a expression was induced both in vitro and in vivo after Mycobacterium bovis BCG infection. The inducible miR-146a could suppress the inducible nitric oxide (NO) synthase (iNOS) expression and NO generation, thus promoting mycobacterial survival in macrophages. Inhibition of endogenous miR-146a increased NO production and mycobacterial clearance. Moreover, miR-146a attenuated the activation of nuclear factor κB and mitogen-activated protein kinases signaling pathways during BCG infection, which in turn repressed iNOS expression. Mechanistically, miR-146a directly targeted tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) at post-transcriptional level. Silencing TRAF6 decreased iNOS expression and NO production in BCG-infected macrophages, while overexpression of TRAF6 reversed miR-146a-mediated inhibition of NO production and clearance of mycobacteria. Therefore, we demonstrated a novel role of miR-146a in the modulation of host defense against mycobacterial infection by repressing NO production via targeting TRAF6, which may provide a promising therapeutic target for tuberculosis.