The NLRP3 inflammasome plays a role in the inflammatory response to vaccines, in antimicrobial host defense, and in autoimmune diseases. However, its mechanism of action remains incompletely understood. NLRP3 has been shown to be activated by diverse stimuli including microbial toxins, ATP, particulate matter, etc. that activate multiple cellular processes. There have been two major challenges in translating inflammasome activators into controlled adjuvants. Both stem from their chemical and structural diversity. First, it is difficult to identify a minimum requirement for inflammasome activation. Second, no current activator can be tuned to generate a desired degree of activation. Thus, in order to design such immunomodulatory biomaterials, we developed a new tunable lysosomal rupture probe that leads to significant differences in inflammasome activation owing to structural changes as small as a single amino acid. Using these probes, we conduct experiments that suggest that rupturing lysosomes is a critical, initial step necessary to activate an inflammasome and that it precedes other pathways of activation. We demonstrate that each molecule differentially activates the inflammasome based solely on their degree of lysosomal rupture. We have employed this understanding of chemical control in structure-based design of immunomodulatory NLRP3 agonists on a semipredictive basis. This information may guide therapeutic interventions to prevent or mitigate lysosomal rupture and will also provide a predictive framework for dosable activation of the NLRP3 inflammasome for potential applications in vaccines and immunotherapies.

中文翻译：

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NLRP3炎性小体的免疫调节通过基于结构的激活剂设计和通过溶酶体破裂的功能调节。

NLRP3炎性小体在疫苗的炎症反应，抗微生物宿主防御以及自身免疫性疾病中发挥作用。但是，其作用机理仍未完全理解。NLRP3已被多种刺激物激活，包括激活多种细胞过程的微生物毒素，ATP，颗粒物等。在将炎性体激活剂转化为受控佐剂中存在两个主要挑战。两者都源于它们的化学和结构多样性。首先，很难确定激活炎症小体的最低要求。第二，没有任何电流激活器可以调节以产生期望的激活程度。因此，为了设计这种免疫调节生物材料，我们开发了一种新型的可调溶酶体破裂探针，该探针由于结构变化小至单个氨基酸而导致了炎性体激活的显着差异。使用这些探针，我们进行的实验表明，溶酶体破裂是激活炎症小体所必需的关键，初始步骤，并且它先于其他激活途径。我们证明，每个分子仅根据其溶酶体破裂的程度就可以不同地激活炎症小体。在半预测的基础上，我们在对免疫调节性NLRP3激动剂的基于结构的设计中采用了对化学控制的理解。