MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway
MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway
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DOI：
10.1016/j.chom.2015.01.007
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发表时间：
2015-03-11
影响因子：
30.3
通讯作者：
Basu, Joyoti
中科院分区：
文献类型：
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作者：
Kumar, Manish;Sahu, Sanjaya Kumar;Basu, Joyoti
结核分枝杆菌（Mtb）与巨噬细胞相互作用的结果取决于宿主防御和细菌免疫颠覆机制之间的相互作用。microrna对几种宿主防御机制有重要的调控作用，但它们在巨噬细胞与巨噬细胞相互作用中的作用尚不清楚。Mtb感染巨噬细胞的MicroRNA谱显示miR-let-7f的下调依赖于Mtb分泌的效应物ESAT-6。我们确定let-7f靶向NF-kappa B通路的反馈抑制剂A20。随着结核分枝杆菌感染的进展，let-7f的表达减少，A20的表达增加。在a20缺陷的巨噬细胞中，Mtb的存活率降低，而作为Mtb免疫介质的TNF、IL-1 β和亚硝酸盐的产生相应增加。此外，let-7f过表达会降低Mtb的存活率，并增加包括TNF和IL-1 β在内的细胞因子的产生。这些结果揭示了let-7f及其靶标A20在调节对Mtb的免疫反应和控制细菌负担中的作用。
The outcome of the interaction between Mycobacterium tuberculosis (Mtb) and a macrophage depends on the interplay between host defense and bacterial immune subversion mechanisms. MicroRNAs critically regulate several host defense mechanisms, but their role in the Mtb-macrophage interplay remains unclear. MicroRNA profiling of Mtb-infected macrophages revealed the downregulation of miR-let-7f in a manner dependent on the Mtb secreted effector ESAT-6. We establish that let-7f targets A20, a feedback inhibitor of the NF-kappa B pathway. Expression of let-7f decreases and A20 increases with progression of Mtb infection in mice. Mtb survival is attenuated in A20-deficient macrophages, and the production of TNF, IL-1 beta, and nitrite, which are mediators of immunity to Mtb, is correspondingly increased. Further, let-7f overexpression diminishes Mtb survival and augments the production of cytokines including TNF and IL-1 beta. These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden.