Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents Burkholderia thailandensis-Induced Multinucleated Giant Cell Formation.
Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents Burkholderia thailandensis-Induced Multinucleated Giant Cell Formation.
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DOI：
10.1128/mbio.02054-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Broz P
中科院分区：
文献类型：
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作者：
Dilucca M;Ramos S;Shkarina K;Santos JC;Broz P
炎性小体是细胞质内的多蛋白信号复合物，在模式识别受体介导的对病原体源配体或内源性危险信号的识别时被激活。它们的组装激活下游炎性的caspase-1和caspase-4/5（人类）或caspase-11（小鼠），通过切割成孔效应的气皮蛋白d诱导细胞因子释放和热亡细胞死亡。宿主细胞的病原体检测也导致干扰素（ifn）的产生和释放，从而微调炎性小体介导的反应。ifn诱导的鸟苷酸结合蛋白（GBPs）已被证明通过在胞质革兰氏阴性菌表面募集caspase-4并促进其与脂多糖（LPS）的相互作用来控制非规范炎性体的激活。革兰氏阴性条件致病菌泰国伯克霍尔德菌感染上皮细胞和巨噬细胞，劫持宿主肌动蛋白聚合机制，向邻近细胞扩散。这个过程导致宿主细胞融合并形成所谓的多核巨细胞（MNGCs）。Caspase-1-和ifn调控的caspase-11介导的炎性小体途径在小鼠体内对泰国芽孢杆菌具有重要的保护作用，但ifn和炎性小体在泰国芽孢杆菌感染人类细胞，特别是上皮细胞中的作用尚不清楚。在这里，我们报道了IFN-γ启动人上皮细胞以gbp1依赖的方式限制泰国芽孢杆菌诱导的MNGC形成。从机制上讲，GBP1不促进细菌溶解或损害基于肌动蛋白的细菌运动，但通过诱导感染细胞的caspase-4依赖性热亡起作用。此外，我们发现IFN-γ启动人原代巨噬细胞通过炎性体激活赋予更有效的抗菌作用，进一步证实了干扰素信号在限制伯克霍尔德菌复制和传播中的重要作用。
Inflammasomes are cytosolic multiprotein signaling complexes that are activated upon pattern recognition receptor-mediated recognition of pathogen-derived ligands or endogenous danger signals. Their assembly activates the downstream inflammatory caspase-1 and caspase-4/5 (human) or caspase-11 (mouse), which induces cytokine release and pyroptotic cell death through the cleavage of the pore-forming effector gasdermin D. Pathogen detection by host cells also results in the production and release of interferons (IFNs), which fine-tune inflammasome-mediated responses. IFN-induced guanylate-binding proteins (GBPs) have been shown to control the activation of the noncanonical inflammasome by recruiting caspase-4 on the surface of cytosolic Gram-negative bacteria and promoting its interaction with lipopolysaccharide (LPS). The Gram-negative opportunistic bacterial pathogen Burkholderia thailandensis infects epithelial cells and macrophages and hijacks the host actin polymerization machinery to spread into neighboring cells. This process causes host cell fusion and the formation of so-called multinucleated giant cells (MNGCs). Caspase-1- and IFN-regulated caspase-11-mediated inflammasome pathways play an important protective role against B. thailandensis in mice, but little is known about the role of IFNs and inflammasomes during B. thailandensis infection of human cells, particularly epithelial cells. Here, we report that IFN-γ priming of human epithelial cells restricts B. thailandensis-induced MNGC formation in a GBP1-dependent manner. Mechanistically, GBP1 does not promote bacteriolysis or impair actin-based bacterial motility but acts by inducing caspase-4-dependent pyroptosis of the infected cell. In addition, we show that IFN-γ priming of human primary macrophages confers a more efficient antimicrobial effect through inflammasome activation, further confirming the important role that interferon signaling plays in restricting Burkholderia replication and spread.