Redox control of the NLRP1 inflammasome

项目摘要 炎性小体检测细胞内与细胞凋亡相关的信号，并触发细胞死亡的炎症形式 叫做焦亡相关的NLRP 1和CARD 8炎性小体感知的危险信号未知 这是一个重大的知识缺口。有趣的是，丝氨酸蛋白酶DPP 8的小分子抑制剂 最近发现DPP 8和DPP 9（DPP 8/9）诱导激活NLRP 1和CARD 8的危险信号 炎性小体然而，与其他炎性体激活剂相反，DPP 8/9抑制剂诱导焦亡 在相对较长的时间内只在一小部分敏感细胞中发生。因此，可能的是， 第二个危险信号与DPP 8/9抑制是完全和快速NLRP 1和CARD 8激活所必需的。 本申请的中心假设是缺乏活性氧物质或还原性应激是导致细胞死亡的原因。 第二个危险信号需要完全激活这些炎性小体。这一假设是根据 申请人实验室提供的初步数据的基础，并在申请中予以描述。很长的- 这个项目的长期目标是了解为什么还原压力是一个危险信号， 先天免疫系统本申请的直接目的是确定分子量。 还原应激激活NLRP 1和CARD 8炎性小体的机制。该项目由 三个具体目标：1）表征氧化剂和抗氧化剂对NLRP 1和CARD 8的影响 活化; 2）确定GPX 1介导的NLRP 1和CARD 8失活的机制;和3） 确定TRX 1如何调节NLRP 1激活。该项目的成功完成将填补一个关键的 通过显示还原性压力是激活NLRP 1和CARD 8的关键危险信号， 炎性小体总的来说，这项工作有巨大的希望揭示一个根本的新的联系， 代谢应激和先天免疫之间的联系，并最终使这些复杂的炎性小体 用于治疗

PROJECT SUMMARY Inflammasomes detect intracellular danger-associated signals and trigger an inflammatory form of cell death called pyroptosis. The danger signals that the related NLRP1 and CARD8 inflammasomes sense are unknown and represent a major knowledge gap. Interestingly, small-molecule inhibitors of the serine proteases DPP8 and DPP9 (DPP8/9) were recently discovered to induce a danger signal that activates the NLRP1 and CARD8 inflammasomes. However, DPP8/9 inhibitors, in contrast to other inflammasome activators, induce pyroptosis in only a fraction of sensitive cells over relatively long time periods. Thus, it is possible that the co-occurrence of a second danger signal with DPP8/9 inhibition is required for full and rapid NLRP1 and CARD8 activation. The central hypothesis of this application is that a lack of reactive oxygen species, or reductive stress, is the second danger signal required to fully activate these inflammasomes. This hypothesis has been formulated on the basis of preliminary data produced in the applicant’s laboratory and described in the application. The long- term goal of this project is to understand why reductive stress is a danger signal that is closely monitored by the innate immune system. The immediate objective of this application is to determine the molecular mechanism by which reductive stress activates the NLRP1 and CARD8 inflammasomes. This project consists of three specific aims: 1) to characterize the impact of oxidants and antioxidants on NLRP1 and CARD8 activation; 2) to determine the mechanism of GPX1-mediated NLRP1 and CARD8 inactivation; and 3) to determine how TRX1 modulates NLRP1 activation. Successful completion of this project will fill a critical knowledge gap by showing that reductive stress is a key danger signal that activates the NLRP1 and CARD8 inflammasomes. Overall, this work holds tremendous promise to reveal a fundamental new connection between metabolic stress and innate immunity, and to eventually enable these complex inflammasomes to be harnessed for therapeutic benefit.