Macrophages are major pathogen-killing cells. Mycobacteria can represent a serious threat to human health, in particular Mycobacterium tuberculosis and, less so, the opportunistic Mycobacterium avium. They can cause disseminated infections because of their capacity to survive and proliferate within macrophage phagolysosomes. Accumulating evidence indicates that the regulation of miRNA expression is implicated in the mechanisms of defense of macrophages against mycobacterial infections. Nevertheless, the precise contribution of miRNAs is largely unknown. The present study analyzes the expression profile of miRNAs during M. avium infection of macrophages by means of microarrays. We detected that the levels of 23 miRNAs were significantly changed ≥2.5-fold 24 h after M. avium infection. In particular, MiR-125a-5p was found to be highly expressed as part of the known immunological response of macrophages to bacterial or viral infections. MiR-125a-5p overexpression inhibited the expression of target signal transducers and activators of transcription 3 (STAT3) in THP-1 cells. Conversely, inhibitors of miR-125a-5p had the opposite effect. Silencing of STAT3 significantly enhanced the level of autophagy in both uninfected and M. avium-infected cells. Overexpression of miR-125a-5p significantly increased autophagy and decreased M. avium survival within THP-1 cells. Instead, co-transfection with miR-125a-5p mimic and a human STAT3 expressing construct reversed the effects: autophagy decreased and intracellular bactericidal survival was improved. Taken together, our findings indicate that miR-125a-5p participates in the regulation of innate host defenses by targeting STAT3 and enhancing autophagy levels. The results reported here contribute to a better understanding of host defense mechanisms against mycobacterial infections and offer some clues about their control.

中文翻译：

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在鸟分枝杆菌感染的巨噬细胞中，miR-125a-5p的水平发生了变化，并与自噬反应的触发有关。

巨噬细胞是主要的杀死病原体的细胞。分枝杆菌可能对人类健康构成严重威胁，尤其是结核分枝杆菌，而机会禽分枝杆菌则对人类健康构成严重威胁。它们可以在巨噬细胞吞噬溶酶体内生存和增殖，因此会引起传播性感染。越来越多的证据表明，miRNA表达的调节与巨噬细胞抵抗分枝杆菌感染的机制有关。然而，miRNA的精确贡献在很大程度上尚不清楚。本研究通过微阵列分析了鸟卵分枝杆菌感染巨噬细胞期间miRNA的表达谱。我们检测到鸟分枝杆菌感染后24小时，≥23倍的23个miRNA的水平发生了显着变化。特别是，发现MiR-125a-5p作为巨噬细胞对细菌或病毒感染的已知免疫反应的一部分而高表达。MiR-125a-5p的过表达抑制了THP-1细胞中目标信号转导子和转录激活因子3（STAT3）的表达。相反，miR-125a-5p抑制剂的作用相反。STAT3沉默显着提高了未感染和鸟分枝杆菌感染细胞的自噬水平。miR-125a-5p的过表达显着增加了THP-1细胞内的自噬并降低了鸟分枝杆菌的存活。相反，与miR-125a-5p模拟物和表达人STAT3的构建体共转染可逆转这种作用：自噬减少，细胞内杀菌存活率提高。在一起 我们的发现表明，miR-125a-5p通过靶向STAT3和增强自噬水平来参与先天宿主防御的调节。此处报道的结果有助于更好地理解宿主对抗分枝杆菌感染的防御机制，并提供有关其控制的一些线索。