Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire.
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire.
Transl Res. 2023 Feb;252:21-33. doi: 10.1016/j.trsl.2022.08.006. Epub 2022 Aug 8.
Neurodegenerative diseases are characterized by a dysregulated neuro-glial microenvironment, culminating in functional deficits resulting from neuronal cell death. Inflammation is a hallmark of the neurodegenerative microenvironment and despite a critical role in tissue homeostasis, increasing evidence suggests that chronic inflammatory insult can contribute to progressive neuronal loss. Inflammation has been studied in the context of neurodegenerative disorders for decades but few anti-inflammatory treatments have advanced to clinical use. This is likely due to the related challenges of predicting and mitigating off-target effects impacting the normal immune response while detecting inflammatory signatures that are specific to the progression of neurological disorders. Inflammasomes are pro-inflammatory cytosolic pattern recognition receptors functioning in the innate immune system. Compelling pre-clinical data has prompted an intense interest in the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in neurodegenerative disease. NLRP3 is typically inactive but can respond to sterile triggers commonly associated with neurodegenerative disorders including protein misfolding and aggregation, mitochondrial and oxidative stress, and exposure to disease-associated environmental toxicants. Clear evidence of enhanced NLRP3 inflammasome activity in common neurodegenerative diseases has coincided with rapid advancement of novel small molecule therapeutics making the NLRP3 inflammasome an attractive target for near-term interventional studies. In this review, we highlight evidence from model systems and patients indicating inflammasome activity in neurodegenerative disease associated with the NLRP3 inflammasome's ability to recognize pathologic forms of amyloid-β, tau, and α-synuclein. We discuss inflammasome-driven pyroptotic processes highlighting the potential utility of evaluating extracellular inflammasome-related proteins in the context of biomarker discovery. We complete the report by pointing out gaps in our understanding of intracellular modifiers of inflammasome activity and mechanisms regulating the resolution of inflammasome activation. The literature review and perspectives provide a conceptual platform for continued analysis of inflammation in neurodegenerative diseases through the study of inflammasomes and pyroptosis, mechanisms of inflammation and cell death now recognized to function in multiple highly prevalent neurological disorders.
神经退行性疾病的特征是神经胶质细胞微环境失调，最终导致神经元细胞死亡引起的功能缺陷。炎症是神经退行性微环境的标志，尽管在组织稳态中起着关键作用，但越来越多的证据表明，慢性炎症损伤可能导致进行性神经元丧失。几十年来，炎症一直在神经退行性疾病的背景下进行研究，但很少有抗炎治疗方法进展到临床应用。这可能是由于预测和减轻对正常免疫反应有影响的脱靶效应的相关挑战，同时检测到特定于神经退行性疾病进展的炎症特征。炎性小体是在固有免疫系统中发挥作用的促炎细胞溶质模式识别受体。令人信服的临床前数据促使人们对 NLR 家族包含吡啶结构域的 3 (NLRP3)炎性小体在神经退行性疾病中的作用产生了浓厚的兴趣。NLRP3 通常处于非活动状态，但可以对与神经退行性疾病相关的常见无菌触发因素作出反应，包括蛋白质错误折叠和聚集、线粒体和氧化应激以及暴露于与疾病相关的环境毒物。在常见神经退行性疾病中增强的 NLRP3 炎性小体活性的明确证据与新型小分子治疗方法的快速进展同时出现，这使得 NLRP3 炎性小体成为近期干预性研究的有吸引力的靶点。在这篇综述中，我们强调了来自模型系统和患者的证据，表明神经退行性疾病相关的炎性小体活性与 NLRP3 炎性小体识别病理性形式的淀粉样蛋白-β、tau 和 α-突触核蛋白的能力有关。我们讨论了炎性小体驱动的细胞焦亡过程，强调了在生物标志物发现的背景下评估细胞外炎性小体相关蛋白的潜在效用。我们通过指出我们对细胞内炎性小体活性调节剂和调节炎性小体激活消退的机制的理解中的差距来完成报告。文献综述和观点为通过研究炎性小体和细胞焦亡、炎症和细胞死亡的机制，在神经退行性疾病中继续分析炎症提供了一个概念平台，这些机制现在被认为在多种高度流行的神经退行性疾病中发挥作用。
