Study of the Cell-specific Inflammasome Responses During Defense Against Gram-negative Bacteria

项目摘要/摘要 常驻巨噬细胞通常是第一个检测到组织细菌污染的细胞，并使用 炎症性半胱氨酸酶，如caspase-1和-11，用于区分毒力细菌和无毒细菌。什么时候 被检测病理性细菌活性的传感器激活，Caspase-1处理前IL-1β和前IL-1 18到它们成熟和分泌的形式，以招募额外的免疫细胞。此外，caspase-1还 引发一种称为下垂的程序性细胞死亡的溶解形式。相反，caspase-11诱导 上睑下垂，但不能单独处理前IL-1β或IL-18。 中性粒细胞是早期感染部位招募的一种主要细胞类型。然而，中性粒细胞是否也 表达炎性半胱氨酸酶以检测细菌毒力仍不清楚。有趣的是， 中性粒细胞表达许多模式识别受体和caspase上游的感受器，但他们的 在感染中的作用还没有得到彻底的研究。 鉴于巨噬细胞中炎性小体的重要性，以及中性粒细胞在 在消毒感染的过程中，中性粒细胞很可能也会使用炎性小体来调节他们对感染的反应。 事实上，我们发现中性粒细胞caspase-11被激活并清除感染的中性粒细胞 效率。因此，在这项研究中，我们建议比较和对比炎症体信号通路。 在中性粒细胞和巨噬细胞中，并确定炎症小体在每个细胞室中的作用 在防御细胞内和细胞外感染期间。确定炎性小体在疾病中的作用 中性粒细胞可能为研究中性粒细胞在感染过程中的功能提供新的视角，以及 洞察潜在的新的和创新的治疗策略，旨在预防胞浆感染 中性粒细胞。

Project Summary/Abstract Resident macrophages are often the first cells to detect bacterial contamination of a tissue, and use inflammatory caspases such as caspases-1 and -11 to distinguish virulent from avirulent bacteria. When activated by sensors that detect pathological bacterial activity, caspase-1 processes pro-IL-1β and pro-IL- 18 to their mature and secreted forms to recruit additional immune cells. In addition, caspase-1 also triggers a lytic form of programmed cell death called pyroptosis. In contrast, caspase-11 induces pyroptosis, but cannot process pro-IL-1β or IL-18 alone. Neutrophils are a major cell type recruited to early sites of infection. However, whether neutrophils also express inflammatory caspases in order to detect bacterial virulence remains unclear. Intriguingly, neutrophils express numerous pattern recognition receptors and sensors upstream of caspases, but their function in infection has not been thoroughly studied. Given the importance of inflammasomes in macrophages, and the importance of neutrophils in sterilizing infection, it is likely that neutrophils also use inflammasomes to tune their responses to infection. Indeed, we found that neutrophil caspase-11 is activated and clears infected neutrophils with extreme efficiency. Thus, in this grant, we propose to compare and contrast the inflammasome signaling pathways in neutrophils and macrophages, and determine the role of inflammasome in each cellular compartment during defense against intracellular and extracellular infection. Determining the role of inflammasomes in neutrophils may provide new perspectives about the function of neutrophils during infection, as well as insight into potentially novel and innovative therapeutic strategies aimed at preventing cytosolic infection in neutrophils.