Redox control of the NLRP1 inflammasome

项目总结 炎症体检测细胞内与危险相关的信号，并触发炎症形式的细胞死亡 叫做下垂。相关的NLRP1和CARD8炎症体感知的危险信号未知 并代表着一个重大的知识鸿沟。有趣的是，丝氨酸蛋白酶DPP8的小分子抑制剂 和DPP9(DPP8/9)最近被发现可以诱导一个危险信号，激活NLRP1和CARD8 炎症性小体。然而，与其他炎性小体激活剂不同的是，DPP8/9抑制剂会导致下垂 只有一小部分敏感细胞在相对较长的时间内。因此，有可能同时发生 NLRP1和CARD8的完全和快速激活需要具有DPP8/9抑制的第二危险信号。 这一应用的中心假设是，缺乏活性氧物种，或还原压力，是 需要第二个危险信号才能完全激活这些炎症体。这一假说是在 申请人实验室提供并在申请书中描述的初步数据的基础。长的- 本项目的学期目标是理解为什么减少压力是一种危险信号，由 先天免疫系统。这一应用的直接目标是确定分子 还原应激激活NLRP1和CARD8炎性小体的机制。该项目包括 有三个具体目的：1)表征氧化剂和抗氧化剂对NLRP1和CARD8的影响 激活；2)确定GPX1介导的NLRP1和CARD8失活的机制；3) 确定TRX1如何调节NLRP1的激活。该项目的成功完成将填补一个关键的 知识鸿沟，表明还原应激是激活NLRP1和CARD8的关键危险信号 炎症性小体。总体而言，这项工作具有巨大的希望，可以揭示一种基本的新联系 代谢应激和先天免疫之间的关系，并最终使这些复杂的炎症体 被利用来治疗的好处。

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.