Different Signaling Pathways Define Different Interferon-Stimulated Gene Expression during Mycobacteria Infection in Macrophages
Different Signaling Pathways Define Different Interferon-Stimulated Gene Expression during Mycobacteria Infection in Macrophages
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DOI：
10.3390/ijms20030663
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发表时间：
2019-02
影响因子：
5.6
通讯作者：
Xinying Zhou;Jiahui Yang;Zelin Zhang;Lijie Zhang;Bo Zhu;Linmiao Lie;Yubin Huang;Rui Ma;Chaoying Zhou;Shengfeng Hu;Q. Wen;Li Ma
中科院分区：
文献类型：
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作者：
Xinying Zhou;Jiahui Yang;Zelin Zhang;Lijie Zhang;Bo Zhu;Linmiao Lie;Yubin Huang;Rui Ma;Chaoying Zhou;Shengfeng Hu;Q. Wen;Li Ma
由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（tuberculosis，TB）是对人类健康的最大威胁之一。干扰素（IFN）与一线抗结核药物的组合已在临床上用于治疗结核病数十年，但结核分枝杆菌感染如何调节人巨噬细胞（Mtb）中的干扰素刺激基因（ISG）仍然未知。在这项研究中，我们研究了ISG在结核分枝杆菌感染的人单核细胞衍生的M β细胞（hMDM）和THP-1衍生的M β细胞（THP-1-M β细胞）中的表达特征和相关的先天信号传导机制。在检测到的28个ISG中，90%的ISG表现出Mtb感染的M β的显著增加。此外，我们还发现胞浆环（GMP-AMP）合酶（cGAS）、TLR-2和TLR-4信号通路参与了ISG的诱导。它们的下游元件TANK结合激酶1（TBK 1）、核因子-κ B（NF-κB）、丝裂原活化蛋白激酶（MAPK）和Janus激酶-信号转导子和转录激活子（JAK-STAT）选择性地参与Mtb介导的ISG产生。最后，结核病患者hMDM中多种类型的ISG表达比健康人更容易受到Mtb感染或/和IFN治疗的再刺激。因此，不同的信号传导途径定义了Mtb感染期间不同的ISG表达，这有助于说明ISG是如何阐明的，并更好地理解宿主对Mtb感染的免疫应答。
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) represents one of the greatest threats to human health., Interferons (IFNs) in combination with the first-line of anti-TB drugs have been used for treating TB for decades in the clinic, but how Mtb infection regulates interferon-stimulated genes (ISGs) in human macrophages (Mϕs) remains unknown. In this study, we investigated the expression-signature and associated innate signaling mechanisms of ISGs in Mtb-infected human monocyte-derived Mϕs (hMDMs) and THP-1-derived Mϕs (THP-1-Mϕs). Among 28 of the detected ISGs, 90% of them exerted a significant increase in Mtb-infected Mϕs. Additionally, we found that cytosolic cyclic (GMP-AMP) synthase (cGAS), toll-like receptor-2 (TLR-2) and TLR-4 signaling pathways participated in ISG induction. Their downstream elements of TANK-binding kinase 1 (TBK1), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducer and activator of transcription (JAK-STAT) were selectively involved in Mtb-mediated ISG production. Finally, the numerous types of ISG expression in hMDMs of TB patients were more susceptible to restimulation of Mtb infection or/and IFN treatment than that of healthy people. Hence, different signaling pathways define different ISG expression during Mtb infection and this helps to illustrate how ISGs are elucidated and to better understand the host immune responses to Mtb infection in Mϕs.