Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins.
Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins.
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DOI：
10.1128/mbio.01188-17
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发表时间：
2017-10-03
期刊：
影响因子：
6.4
通讯作者：
Coers J
中科院分区：
文献类型：
--
作者：
Finethy R;Luoma S;Orench-Rivera N;Feeley EM;Haldar AK;Yamamoto M;Kanneganti TD;Kuehn MJ;Coers J
革兰氏阴性细菌细胞壁组分脂多糖（LPS）被感染的宿主细胞的胞质溶胶中的非典型炎性体蛋白胱天蛋白酶-11识别，从而促进与脓毒症相关的炎性免疫应答。在组织培养模型中，宿主鸟苷酸结合蛋白（GBP）促进感染诱导的caspase-11活化，但它们在LPS介导的脓毒症中的体内作用尚未研究。LPS可以作为“游离”LPS聚集体从裂解的细菌中释放，或者作为外膜囊泡（OMV）的组分由活细菌主动分泌。在这里，我们报告说，GBP控制炎症和败血症的小鼠注射游离LPS或纯化OMV来自革兰氏阴性大肠杆菌。与我们在体内实验中的观察结果一致，我们证明了当暴露于OMV时，缺乏GBP 2表达的巨噬细胞不能诱导热凋亡细胞死亡和促炎性白细胞介素-1 β（IL-1β）和IL-18分泌。我们提出，为了在体内激活caspase-11，GBP控制巨噬细胞对细菌来源的OMV的加工以及尚未确定的细胞类型对循环游离LPS的加工。细菌细胞壁组分LPS是炎症的强烈诱导物，并且是革兰氏阴性菌的大部分毒性的原因。细菌以外膜囊泡（OMV）的形式脱落一些细胞壁及其相关的LPS。最近的工作表明，分泌的OMV通过未知的机制将LPS递送到宿主细胞胞质溶胶中，导致促炎性LPS传感器caspase-11的激活。在这里，我们表明，OMV激活胞浆caspase-11需要额外的宿主因子，即所谓的鸟苷酸结合蛋白（GBP）。GBP作为OMV介导的炎症调节因子的发现为理解宿主对细菌OMV的反应机制铺平了道路，并可能导致改善细菌感染诱导的炎症的有效策略。
The Gram-negative bacterial cell wall component lipopolysaccharide (LPS) is recognized by the noncanonical inflammasome protein caspase-11 in the cytosol of infected host cells and thereby prompts an inflammatory immune response linked to sepsis. Host guanylate binding proteins (GBPs) promote infection-induced caspase-11 activation in tissue culture models, and yet their in vivo role in LPS-mediated sepsis has remained unexplored. LPS can be released from lysed bacteria as “free” LPS aggregates or actively secreted by live bacteria as a component of outer membrane vesicles (OMVs). Here, we report that GBPs control inflammation and sepsis in mice injected with either free LPS or purified OMVs derived from Gram-negative Escherichia coli. In agreement with our observations from in vivo experiments, we demonstrate that macrophages lacking GBP2 expression fail to induce pyroptotic cell death and proinflammatory interleukin-1β (IL-1β) and IL-18 secretion when exposed to OMVs. We propose that in order to activate caspase-11 in vivo, GBPs control the processing of bacterium-derived OMVs by macrophages as well as the processing of circulating free LPS by as-yet-undetermined cell types. The bacterial cell wall component LPS is a strong inducer of inflammation and is responsible for much of the toxicity of Gram-negative bacteria. Bacteria shed some of their cell wall and its associated LPS in the form of outer membrane vesicles (OMVs). Recent work demonstrated that secreted OMVs deliver LPS into the host cell cytosol by an unknown mechanism, resulting in the activation of the proinflammatory LPS sensor caspase-11. Here, we show that activation of cytosolic caspase-11 by OMVs requires additional host factors, the so-called guanylate binding proteins (GBPs). The discovery of GBPs as regulators of OMV-mediated inflammation paves the way toward a mechanistic understanding of the host response toward bacterial OMVs and may lead to effective strategies to ameliorate inflammation induced by bacterial infections.