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

项目总结/摘要 常驻巨噬细胞通常是检测组织的细菌污染的第一个细胞，并且使用 炎性半胱天冬酶，如半胱天冬酶-1和-11，以区分毒性细菌和无毒力细菌。当 通过检测病理性细菌活性的传感器激活，caspase-1处理pro-IL-1β和pro-IL-1 β。 18至其成熟和分泌形式以募集额外的免疫细胞。此外，caspase-1还 引发了一种裂解性的程序性细胞死亡叫做细胞凋亡相反，caspase-11诱导 细胞凋亡，但不能单独处理IL-1β原或IL-18。 中性粒细胞是募集到感染早期部位的主要细胞类型。然而，中性粒细胞是否也 表达炎性半胱天冬酶以检测细菌的毒力仍不清楚。有趣的是， 中性粒细胞表达许多模式识别受体和半胱天冬酶上游的传感器，但它们的 在感染中的作用还没有被彻底研究。 鉴于巨噬细胞中炎性小体的重要性，以及中性粒细胞在巨噬细胞中的重要性， 除了消灭感染外，中性粒细胞也可能利用炎性小体来调节它们对感染的反应。 事实上，我们发现中性粒细胞半胱天冬酶-11被激活，并清除感染的中性粒细胞， 效率因此，在本研究中，我们建议比较和对比炎性小体信号通路 在中性粒细胞和巨噬细胞中，并确定炎性小体在每个细胞区室中的作用 在防御细胞内和细胞外感染的过程中。确定炎性小体在 嗜中性粒细胞可能提供关于感染过程中嗜中性粒细胞功能的新观点，以及 深入了解潜在的新的和创新的治疗策略，旨在预防细胞溶质感染， 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.