TLR-4/miRNA-32-5p/FSTL1 signaling regulates mycobacterial survival and inflammatory responses in Mycobacterium tuberculosis -infected macrophages

生物 结核分枝杆菌 小RNA 下调和上调 免疫系统 肺结核 免疫印迹 细胞内 微生物学 分枝杆菌 免疫学 巨噬细胞 细胞因子 U937电池 细胞生物学 细胞培养 体外 医学 细菌 基因 生物化学 病理 遗传学
作者
Zhimin Zhang,Ai-Rong Zhang,Min Xu,Jun Lou,Weiqiang Qiu
出处
期刊:Experimental Cell Research [Elsevier]
卷期号:352 (2): 313-321 被引量:55
标识
DOI:10.1016/j.yexcr.2017.02.025
摘要

Macrophages play a pivotal role in host immune response against mycobacterial infection, which is tightly modulated by multiple factors, including microRNAs. The purpose of the present study was to investigate the biological function and potential mechanism of miR-32-5p in human macrophages during Mycobacterium tuberculosis (M.tb) infection. The results demonstrated that miR-32-5p was robustly enhanced in THP-1 and U937 cells in response to M.tb infection. TLR-4 signaling was required for upregulation of miR-32-5p induced by M.tb infection. Additionally, the introduction of miR-32-5p strongly increased the survival rate of intracellular mycobacteria, whereas inhibition of miR-32-5p suppressed intracellular growth of mycobacteria during M.tb challenged. Furthermore, forced expression of miR-32-5p dramatically attenuated the accumulation of inflammatory cytokines IL-1β, IL-6 and TNF-α induced by M.tb infection. Conversely, downregulated expression of miR-32-5p led to enhancement in these inflammatory cytokines. More importantly, our study explored that Follistatin-like protein 1 (FSTL1) was a direct and functional target of miR-32-5p. qRT-PCR and western blot analysis further validated that miR-32-5p negatively regulated the expression of FSTL1. Mechanistically, re-expression of FSTL1 attenuated the ability of miR-32-5p to promote mycobacterial survival. Meanwhile, miR-32-5p-mediated inhibition of the inflammatory cytokine production were completely reversed by overexpression of FSTL1. Collectively, our findings demonstrated a novel role of TLR-4/miRNA-32-5p/FSTL1 in the modulation of host defense against mycobacterial infection, which may provide a better understanding of the pathogenesis of tuberculosis and useful information for developing potential therapeutic interventions against the disease.
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