炎症小体激活：从分子机制到自身炎症,Clinical & Translational Immunology

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炎症小体激活：从分子机制到自身炎症
Clinical & Translational Immunology ( IF 4.6 ) Pub Date : 2022-07-07 , DOI: 10.1002/cti2.1404
Samuel Lara-Reyna ₁ , Emily A Caseley ₂ , Joanne Topping ₃ , François Rodrigues ₄ , Jorge Jimenez Macias _{5,

6} , Sean E Lawler _{5,

6} , Michael F McDermott ₃

Affiliation

炎症小体由先天免疫传感器组装而成，细胞利用这些传感器检测一系列危险信号并以促炎信号作出反应。炎性体激活炎性半胱天冬酶，引发一系列分子事件，有可能损害细胞完整性并释放 IL-1β 和 IL-18 促炎细胞因子。几种分子机制协同工作，确保炎性体激活受到严格调节；这些包括 NLRP3 翻译后修饰、泛素化和磷酸化，以及与关键炎性体成分竞争性结合的单域蛋白，例如 CARD-only 蛋白 (COPs) 和 PYD-only 蛋白 (POPs)。这些多样化的调节系统确保启动适当水平的炎症以抵消任何细胞损伤，同时保留组织结构。当炎症小体被异常激活时，会导致促炎细胞因子的过度产生和细胞死亡，从而导致组织损伤。在几种自身炎症条件下，炎症小体被异常激活，随后出现反映潜在组织和器官损伤程度的临床特征。除了最近开发的小分子抑制剂外，一些由此产生的疾病并发症可以通过抗炎药和/或特定细胞因子抑制剂成功控制。在这篇综述中，我们将探索几种炎症小体激活的分子过程，并强调它们在健康和疾病中的作用。我们还描述了这些炎性体复合物的有害影响，

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Inflammasome activation: from molecular mechanisms to autoinflammation

Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro-inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL-1β and IL-18 pro-inflammatory cytokines. Several molecular mechanisms, working in concert, ensure that inflammasome activation is tightly regulated; these include NLRP3 post-translational modifications, ubiquitination and phosphorylation, as well as single-domain proteins that competitively bind to key inflammasome components, such as the CARD-only proteins (COPs) and PYD-only proteins (POPs). These diverse regulatory systems ensure that a suitable level of inflammation is initiated to counteract any cellular insult, while simultaneously preserving tissue architecture. When inflammasomes are aberrantly activated can drive excessive production of pro-inflammatory cytokines and cell death, leading to tissue damage. In several autoinflammatory conditions, inflammasomes are aberrantly activated with subsequent development of clinical features that reflect the degree of underlying tissue and organ damage. Several of the resulting disease complications may be successfully controlled by anti-inflammatory drugs and/or specific cytokine inhibitors, in addition to more recently developed small-molecule inhibitors. In this review, we will explore the molecular processes underlying the activation of several inflammasomes and highlight their role during health and disease. We also describe the detrimental effects of these inflammasome complexes, in some pathological conditions, and review current therapeutic approaches as well as future prospective treatments.

更新日期：2022-07-08

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