Regulation of the physiologic and pathologic activation of the NLRP3-inflammasome

描述(由申请人提供)：识别病原体并启动炎症和免疫过程以控制其传播的能力依赖于天然免疫系统信号。最近发现的病原体感知信号通路之一涉及炎症体的激活，炎症体是一种大分子复合体，负责对几种未成熟的细胞因子(特别是IL-12和IL-18)进行蛋白质分解处理。在炎症体的组装过程中，ATP结合蛋白NLRP3起着中心支架的作用。除了细胞因子的处理，我们最近发现，通过NLRP3的信号激活了一种新的细胞死亡程序，具有坏死的形态和生化特征。NLRP3-炎症体可以被许多已知诱导IL-12分泌的刺激激活，这表明NLRP3的生理作用是整合对一系列促炎触发因素的反应。NLRP3核苷酸结合域的突变可导致遗传性周期性发热综合征。我们最近还发现，金黄色葡萄球菌的一些关键毒力因子也激活了NLRP3炎症体。表达这些毒力因子的金黄色葡萄球菌可导致以全身炎症反应和组织坏死为特征的严重坏死性肺炎。我们认为，由突变和病原体去毒力因子激活的NLRP3代表了导致与这些刺激相关的失调炎症和进展性疾病的病理事件。我们现在建议进一步研究调控NLRP3激活的分子机制及其在金黄色葡萄球菌感染发病机制中的作用。这些研究将为理解炎症信号过程提供关键信息，这些信号过程涉及一系列巨大的人类疾病的发病机制。 公共卫生相关性：我们已经发现，来自耐甲氧西林金黄色葡萄球菌(MRSA)的几个毒力因子激活了一种被称为炎症体的先天性免疫信号复合体。我们建议开展研究，以了解炎症小体激活宿主炎症如何影响MRSA感染的发病机制。我们还建议对炎症小体激活的基础机制进行详细研究，这可能会确定药物开发的靶点，从而改善这些致命感染的治疗。

DESCRIPTION (provided by applicant): The ability to recognize pathogens and initiate inflammatory and immunologic processes to control their spread relies on innate immune system signaling. One of the most recently identified pathogen-sensing signaling pathways involves the activation of the inflammasome, a macromolecular complex responsible for proteolytic processing of several immature cytokines (IL- 12 and IL-18 in particular). The ATP-binding protein NLRP3 acts as a central scaffold during in the assembly of the inflammasome. In addition to cytokine processing, we have recently found that signaling through NLRP3 activates a novel cell death program with morphologic and biochemical features of necrosis. The NLRP3-inflammasome can be activated by numerous stimuli known to induce IL-12 secretion, suggesting that the physiologic role of NLRP3 is to integrate the response to a range of pro-inflammatory triggers. Mutations in the nucleotide-binding domain of NLRP3 can cause inherited periodic fever syndromes. We have also recently discovered that some critical virulence factors from Staphylococcus aureus activate the NLRP3 inflammasome as well. S. aureus that express these virulence factors can cause with severe necrotizing pneumonias that are characterized by systemic inflammatory response and tissue necrosis. We believe activation of NLRP3 by mutation and pathogen-dervived virulence factors represent pathologic events that lead to dysregulated inflammation and progression diseases associated with these stimuli. We now propose to further investigate both the molecular mechanisms regulating NLRP3 activation and its role in the pathogenesis of S. aureus infections. These studies will provide crucial information in understanding inflammatory signaling processes involved in the pathogenesis of a huge array of human diseases. PUBLIC HEALTH RELEVANCE: We have found that several virulence factors from Methicillin Resistant S. aureus (MRSA) activate an innate immune signaling complex known as the inflammasome. We propose to carry out studies to understand how activation of host inflammation by the inflammasome affects the pathogenesis of MRSA infections. We also propose detailed studies into the mechanism that underlies activation of the inflammasome, which may identify targets for the development of pharmacologic agents that could improve the treatment of these deadly infections.