Beneficial bacteria activate type-I interferon production via the intracellular cytosolic sensors STING and MAVS.
Beneficial bacteria activate type-I interferon production via the intracellular cytosolic sensors STING and MAVS.
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DOI：
10.1080/19490976.2019.1707015
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发表时间：
2020-07-03
期刊：
影响因子：
12.2
通讯作者：
Maluquer De Motes C
中科院分区：
文献类型：
--
作者：
Gutierrez-Merino J;Isla B;Combes T;Martinez-Estrada F;Maluquer De Motes C
I型干扰素（IFN-I）细胞因子由免疫细胞响应于微生物感染、癌症和自身免疫性疾病而产生，并且随后通过IFN-I刺激的基因（ISG）的激活来触发细胞保护和抗病毒应答。肠道微生物群调节先天免疫应答的能力是众所周知的，但这种应答的机制仍然难以捉摸。在这里，我们报告了IFN基因（STING）和线粒体抗病毒信号转导（MAVS）的细胞内传感器刺激因子对乳酸菌（LAB），具有有益特性的普通肠道细菌产生IFN-I至关重要。使用人巨噬细胞，我们表明，有效激活炎症转录因子NF-κB的LAB菌株是IFN-I的不良诱导剂，相反，那些触发大量IFN-I的菌株不能激活NF-κB。在人原代巨噬细胞中也观察到这种IFN-I应答，所述巨噬细胞在用IFN-I诱导的LAB攻击后调节CD 64和CD 40。从机制上讲，与NF-κ B诱导剂相比，IFN-I诱导剂与吞噬细胞的相互作用更密切，并且在存在吞噬抑制剂的情况下不能激活IFN-I。然后，这些细菌在细胞内被细胞质传感器STING感测，并且在较小程度上被MAVS感测。因此，缺乏STING的巨噬细胞显示出TANK结合激酶（TBK）-1的磷酸化和IFN-I活化的显著降低，这导致ISG的表达降低。我们的研究结果证明了细胞内传感和STING在有益细菌产生IFN-I中的重要作用，以及细菌特异性免疫特征的存在，其可用于促进细胞保护反应并防止肠道中过度反应的NF-κ B依赖性炎症。
Type-I interferon (IFN-I) cytokines are produced by immune cells in response to microbial infections, cancer and autoimmune diseases, and subsequently, trigger cytoprotective and antiviral responses through the activation of IFN-I stimulated genes (ISGs). The ability of intestinal microbiota to modulate innate immune responses is well known, but the mechanisms underlying such responses remain elusive. Here we report that the intracellular sensors stimulator of IFN genes (STING) and mitochondrial antiviral signaling (MAVS) are essential for the production of IFN-I in response to lactic acid bacteria (LAB), common gut commensal bacteria with beneficial properties. Using human macrophage cells we show that LAB strains that potently activate the inflammatory transcription factor NF-κB are poor inducers of IFN-I and conversely, those triggering significant amounts of IFN-I fail to activate NF-κB. This IFN-I response is also observed in human primary macrophages, which modulate CD64 and CD40 upon challenge with IFN-I-inducing LAB. Mechanistically, IFN-I inducers interact more intimately with phagocytes as compared to NF-κB-inducers, and fail to activate IFN-I in the presence of phagocytosis inhibitors. These bacteria are then sensed intracellularly by the cytoplasmic sensors STING and, to a lesser extent, MAVS. Accordingly, macrophages deficient for STING showed dramatically reduced phosphorylation of TANK-binding kinase (TBK)-1 and IFN-I activation, which resulted in lower expression of ISGs. Our findings demonstrate a major role for intracellular sensing and STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to promote cytoprotective responses and prevent overreactive NF-κB-dependent inflammation in the gut.
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影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1073/pnas.1107114108
发表时间：
2011-10-18
影响因子：
11.1
作者：
Li, Xiao-Dong;Chiu, Yu-Hsin;Chen, Zhijian J.
通讯作者：
Chen, Zhijian J.
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S
影响因子：
2.1
作者：
KITAZAWA, H;TOMIOKA, Y;YAMAGUCHI, T
通讯作者：
YAMAGUCHI, T
影响因子：
7.3
作者：
Kotredes KP;Thomas B;Gamero AM
通讯作者：
Gamero AM