Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
mBio. 2017 Oct 3;8(5):e01188-17. doi: 10.1128/mBio.01188-17.
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 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 In agreement with our observations from 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 , 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.
革兰氏阴性细菌细胞壁成分脂多糖 (LPS) 在感染宿主细胞的细胞质中被非典型炎性小体蛋白 caspase-11 识别，从而引发与败血症相关的炎症免疫反应。宿主鸟苷酸结合蛋白 (GBP) 在组织培养模型中促进感染诱导的 caspase-11 激活，但它们在 LPS 介导的败血症中的作用仍未被探索。LPS 可以从裂解细菌中释放为“游离”LPS 聚集体，或者作为外膜囊泡 (OMV) 的一部分由活细菌主动分泌。在这里，我们报告说，GBP 在注射游离 LPS 或源自革兰氏阴性细菌的纯化 OMV 的小鼠中控制炎症和败血症。与我们从实验中观察到的结果一致，我们证明当暴露于 OMV 时，缺乏 GBP2 表达的巨噬细胞无法诱导细胞焦亡和促炎白细胞介素-1β (IL-1β) 和白细胞介素-18 的分泌。我们提出，为了激活 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。细菌细胞壁成分 LPS 是炎症的强烈诱导剂，是革兰氏阴性细菌毒性的主要原因。细菌以细胞膜囊泡 (OMV) 的形式脱落部分细胞壁及其相关 LPS。最近的工作表明，分泌的 OMV 通过未知机制将 LPS 递送入宿主细胞细胞质，导致促炎 LPS 传感器 caspase-11 的激活。在这里，我们表明 OMV 激活细胞质 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 介导的炎症调节剂的发现为理解宿主对细菌 OMV 的反应机制铺平了道路，并可能为改善细菌感染引起的炎症提供有效的策略。
