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

防御革兰氏阴性菌过程中细胞特异性炎症反应的研究

基本信息

批准号：
10161251
负责人：
Youssef Aachoui
金额：
$ 25.08万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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.

项目概要/摘要常驻巨噬细胞通常是第一个检测组织细菌污染的细胞，并使用炎症性半胱天冬酶（例如 caspase-1 和 -11）可区分有毒细菌和无毒细菌。 caspase-1 由检测病理性细菌活性的传感器激活，处理 pro-IL-1β 和 pro-IL- 18 以其成熟和分泌的形式来招募额外的免疫细胞此外，caspase-1 也能发挥作用。 caspase-11 会引发一种称为细胞焦亡的裂解形式的程序性细胞死亡。细胞焦亡，但不能单独处理 IL-1β 前体或 IL-18。中性粒细胞是招募到早期感染部位的主要细胞类型，但中性粒细胞也是如此。表达炎症半胱天冬酶以检测细菌毒力仍不清楚。中性粒细胞表达大量半胱天冬酶上游的模式识别受体和传感器，但它们的在感染中的功能尚未得到彻底研究。鉴于炎症小体在巨噬细胞中的重要性以及中性粒细胞在巨噬细胞中的重要性在消灭感染的过程中，中性粒细胞很可能也使用炎性小体来调整其对感染的反应。事实上，我们发现中性粒细胞 caspase-11 被激活并以极端的方式清除受感染的中性粒细胞。因此，在这项资助中，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区室中的作用确定炎症小体在防御细胞内和细胞外感染过程中的作用。中性粒细胞可能为感染期间中性粒细胞的功能提供新的视角，以及深入了解旨在预防细胞质感染的潜在新颖和创新治疗策略中性粒细胞。