Inflammasomes are key regulators of the host response against microbial pathogens, in addition to limiting aberrant responses to sterile insults, as mediated by environmental agents such as toxins or nanoparticles, and also by endogenous danger signals such as monosodium urate, ATP and amyloid-β. To date at least six different inflammasome signalling platforms have been reported (Bauernfeind & Hornung, EMBO Mol Med. 2013;5:814–26; Broz & Dixit, Nat Rev Immunol. 2016;16:407). This review focuses on the complex molecular machinery involved in activation and regulation of the best characterised inflammasome, NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), and the development of molecular agents to modulate NLRP3 inflammasome function. Activation of the NLRP3 inflammasome induces inflammation via secretion of interleukin-1β (IL-1β) and interleukin-18 (IL-18) proinflammatory cytokines, with orchestration of pyroptotic cell death, to eliminate invading microbial pathogens. This field has gradually moved from an emphasis on monogenic autoinflammatory conditions, such as cryopyrin-associated periodic syndromes (CAPS), to the broad spectrum of innate immune-mediated disease. NLRP3 inflammasome activation is also linked to a range of common disorders in humans including type 2 diabetes (Krainer et al., J Autoimmun. 2020:102421), cystic fibrosis (Scambler et al., eLife. 2019;8), myocardial infarction, Parkinson’s disease, Alzheimer’s disease (Savic et al., Nat Rev Rheumatol. 2020:1–16) and cancers such as mesotheliomas and gliomas (Moossavi et al., Mol Cancer. 2018;17:158). We describe how laboratory-based assessment of NLRP3 inflammasome activation is emerging as an integral part of the clinical evaluation and treatment of a range of undifferentiated systemic autoinflammatory disorders (uSAID) (Harrison et al., JCI Insight. 2016;1), where a DNA-based diagnosis has not been possible. In addition, this review summarises the current literature on physiological inhibitors and features various pharmacological approaches that are currently being developed, with potential for clinical translation in autoinflammatory and immune-mediated conditions. We discuss the possibilities of rational drug design, based on detailed structural analyses, and some of the challenges in transferring exciting preliminary results from trials of small-molecule inhibitors of the NLRP3 inflammasome, in animal models of disease, to the clinical situation in human pathology.

炎症小体是宿主针对微生物病原体反应的关键调节因子，除了限制对无菌侵害的异常反应（由环境因素（如毒素或纳米粒子）介导的内源性危险信号，如尿酸钠，ATP和淀粉样β介导的异常反应）。迄今为止，至少已报告了六个不同的炎症小体信号传递平台（Bauernfeind＆Hornung，EMBO Mol Med。2013； 5：814–26； Broz＆Dixit，Nat Rev Immunol。2016； 16：407）。这篇综述着重于复杂的分子机制，涉及最有特征的炎性小体NLRP3（含NOD，LRR和吡喃结构域的蛋白质3）的激活和调节，以及调节NLRP3炎性体功能的分子药物的开发。NLRP3炎性体的激活通过分泌白细胞介素-1β（IL-1β）和白介素-18（IL-18）促炎细胞因子来诱导炎症，并编排了焦细胞凋亡，以消除入侵的微生物病原体。该领域已逐渐从对单基因自身炎性疾病（如冷冻蛋白相关的周期性综合征（CAPS））的关注转移到广泛的先天性免疫介导疾病。NLRP3炎性体激活也与人类的一系列常见疾病有关，包括2型糖尿病（Krainer等人，J Autoimmun。2020：102421），囊性纤维化（Scambler等人，eLife。2019; 8），心肌梗塞，帕金森氏病，阿尔茨海默氏病（Savic等，Nat Rev Rheumatol。2020：1-16）和间皮瘤和神经胶质瘤等癌症（Moossavi等，Mol Cancer。2018; 17：158）。我们描述了基于实验室的NLRP3炎性体激活的评估是如何作为一系列未分化的系统性自身炎性疾病（uSAID）的临床评估和治疗的组成部分而出现的（Harrison et al。，JCI Insight。2016; 1），其中基于DNA的诊断是不可能的。此外，本综述总结了有关生理抑制剂的最新文献，并介绍了目前正在开发的各种药理学方法，它们在自身炎症和免疫介导的情况下具有临床翻译潜力。我们将基于详细的结构分析，讨论合理药物设计的可能性，以及在疾病动物模型中转移NLRP3炎性小分子抑制剂试验的令人振奋的初步结果中的一些挑战，