Abstract：
Neuroinflammation is a key pathophysiological feature of stroke-associated brain injury. A local innate immune response triggers neuroinflammation following a stroke via activating inflammasomes. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has been heavily implicated in stroke pathobiology. Following a stroke, several stimuli have been suggested to trigger the assembly of the NLRP3 inflammasome. Recent studies have advanced the understanding and revealed several new players regulating NLRP3 inflammasome-mediated neuroinflammation. This article discussed recent advancements in NLRP3 assembly and highlighted stroke-induced mitochondrial dysfunction as a major checkpoint to regulating NLRP3 activation. The NLRP3 inflammasome activation leads to caspase-1-dependent maturation and release of IL-1β, IL-18, and gasdermin D. In addition, genetic or pharmacological inhibition of the NLRP3 inflammasome activation and downstream signaling has been shown to attenuate brain infarction and improve the neurological outcome in experimental models of stroke. Several drug-like small molecules targeting the NLRP3 inflammasome are in different phases of development as novel therapeutics for various inflammatory conditions, including stroke. Understanding how these molecules interfere with NLRP3 inflammasome assembly is paramount for their better optimization and/or development of newer NLRP3 inhibitors. In this review, we summarized the assembly of the NLRP3 inflammasome and discussed the recent advances in understanding the upstream regulators of NLRP3 inflammasome-mediated neuroinflammation following stroke. Additionally, we critically examined the role of the NLRP3 inflammasome-mediated signaling in stroke pathophysiology and the development of therapeutic modalities to target the NLRP3 inflammasome-related signaling for stroke treatment.
摘要：
神经炎症是卒中相关脑损伤的关键病理生理特征。局部先天免疫应答通过激活炎性体触发中风后的神经炎症。核苷酸结合寡聚化结构域富含亮氨酸的重复序列和含pyrin结构域的蛋白3（NLRP3）炎性体与中风病理生物学密切相关。中风后，已经提出了几种刺激来触发NLRP3炎性体的组装。最近的研究提高了人们的理解，并揭示了一些调节NLRP3炎症小体介导的神经炎症的新参与者。本文讨论了NLRP3组装的最新进展，并强调了卒中诱导的线粒体功能障碍是调节NLRP3激活的主要检查点。NLRP3炎性体激活导致caspase-1依赖性成熟和IL-1β释放,IL-18和gasderminD。此外，在卒中实验模型中,NLRP3炎性体激活和下游信号传导的遗传或药理学抑制已被证明可减轻脑梗死并改善神经系统预后.靶向NLRP3炎性体的几种药物样小分子正处于不同的发展阶段，作为各种炎症状态的新疗法。包括中风。了解这些分子如何干扰NLRP3炎性体组装对于更好地优化和/或开发新的NLRP3抑制剂至关重要。在这次审查中,我们总结了NLRP3炎性体的组装,并讨论了在了解NLRP3炎性体介导的卒中后神经炎症的上游调节因子方面的最新进展.此外,我们严格研究了NLRP3炎性体介导的信号传导在卒中病理生理学中的作用,以及针对NLRP3炎性体相关信号传导用于卒中治疗的治疗模式的发展.
