Abstract

Inflammasomes are important modulators of inflammation. Dysregulation of inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related to inflammatory and neurodegenerative diseases. NLRP3 is an intracellular sensor that recognizes pathogen-associated molecular patterns and damage-associated patterns resulting in the assembly and activation of NLRP3 inflammasome. The NLRP3 inflammasome includes sensor NLRP3, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 that plays an imperative role in caspase-1 stimulation which further initiates a secondary inflammatory response. Regulation of NLRP3 inflammasome ameliorates NLRP3-mediated diseases. Much effort has been invested in studying the activation, and exploration of specific inhibitors and epigenetic mechanisms controlling NLRP3 inflammasome. This review gives an overview of the established NLRP3 inflammasome assembly, its brief molecular mechanistic activations as well as a current update on specific and non-specific NLRP3 inhibitors that could be used in NLRP3-mediated diseases. We also focused on the recently discovered epigenetic mechanisms mediated by DNA methylation, histone alterations, and microRNAs in regulating the activation and expression of NLRP3 inflammasome, which has resulted in a novel method of gaining insight into the mechanisms that modulate NLRP3 inflammasome activity and introducing potential therapeutic strategies for CNS disorders.

Graphical Abstract

中文翻译：

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NLRP3 炎症小体的新见解：激活、抑制和表观遗传调控机制

摘要

炎症小体是炎症的重要调节剂。炎症小体的失调会增加对神经退行性疾病、自身炎症性疾病和代谢紊乱等疾病的脆弱性。在各种炎症小体中，核苷酸结合寡聚化结构域富含亮氨酸重复序列和含有吡啶结构域的蛋白3（NLRP3）是与炎症和神经退行性疾病相关的最具有特征的炎症小体。NLRP3 是一种细胞内传感器，可识别病原体相关分子模式和损伤相关模式，从而导致 NLRP3 炎性体的组装和激活。NLRP3 炎症小体包括传感器 NLRP3、接头凋亡相关斑点样蛋白 (ASC) 和效应器半胱氨酸蛋白酶 procaspase-1，后者在 caspase-1 刺激中发挥重要作用，进一步引发继发性炎症反应。NLRP3 炎性体的调节可改善 NLRP3 介导的疾病。人们投入了大量的精力来研究激活、探索控制 NLRP3 炎症小体的特异性抑制剂和表观遗传机制。本综述概述了已建立的 NLRP3 炎症小体组装体、其简短的分子机制激活以及可用于 NLRP3 介导的疾病的特异性和非特异性 NLRP3 抑制剂的最新更新。我们还关注了最近发现的由 DNA 甲基化、组蛋白改变和 microRNA 介导的表观遗传机制来调节 NLRP3 炎症小体的激活和表达，这产生了一种新的方法来深入了解调节 NLRP3 炎症小体活性的机制并引入潜在的中枢神经系统疾病的治疗策略。

图形概要