Immunomodulation of the NLRP3 Inflammasome through Structure-Based Activator Design and Functional Regulation via Lysosomal Rupture.
Immunomodulation of the NLRP3 Inflammasome through Structure-Based Activator Design and Functional Regulation via Lysosomal Rupture.
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DOI：
10.1021/acscentsci.8b00218
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发表时间：
2018-08-22
影响因子：
18.2
通讯作者：
Esser-Kahn AP
中科院分区：
文献类型：
--
作者：
Manna S;Howitz WJ;Oldenhuis NJ;Eldredge AC;Shen J;Nihesh FN;Lodoen MB;Guan Z;Esser-Kahn AP
NLRP 3炎性体在对疫苗的炎症反应、抗微生物宿主防御和自身免疫性疾病中起作用。然而，其作用机制仍不完全清楚。NLRP 3已被证明是由多种刺激，包括微生物毒素，ATP，颗粒物质等激活多种细胞过程激活。在将炎性体激活剂转化为受控佐剂方面存在两个主要挑战。两者都源于其化学和结构的多样性。首先，很难确定炎性小体激活的最低要求。其次，没有电流激活器可以被调谐以产生期望程度的激活。因此，为了设计这样的免疫调节生物材料，我们开发了一种新的可调溶酶体破裂探针，其由于小至单个氨基酸的结构变化而导致炎性小体活化的显著差异。使用这些探针，我们进行的实验表明，破裂溶酶体是一个关键的，初始步骤所必需的激活炎性小体，它先于其他途径的激活。我们证明，每个分子差异激活炎性小体完全基于其程度的溶酶体破裂。我们采用这种理解的化学控制的免疫调节NLRP3激动剂的结构为基础的设计半预测的基础上。该信息可以指导治疗干预以预防或减轻溶酶体破裂，并且还将为NLRP 3炎性体的可剂量活化提供预测框架，用于疫苗和免疫疗法中的潜在应用。我们研究了NLRP 3炎性小体激活的最小机制途径。我们已经在受控免疫激活剂的合理设计中采用了这种结构和功能上的理解。
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. We investigated a minimal mechanistic pathway for NLRP3 inflammasome activation. We have employed this structural and functional understanding in rational design of controlled immune activators.
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