基于NLRP3/IL-1β通路探讨自噬功能障碍在偏头痛发病机制中的潜在病理作用

Exploring the Potential Pathological Role of Autophagic Dysfunction in the Pathogenesis of Migraine via the NLRP3/IL-1β Pathway

摘要:

【摘要】偏头痛（migraine）是临床常见的慢性神经血管性疾病，以反复发作性头痛为特征，严重影响患者生活质量。已有大量研究表明，神经炎症在该疾病发生发展中发挥关键作用，其中神经胶质细胞活化是神经炎症的核心环节，可通过释放促炎介质导致神经元损伤。近年来研究证实，三叉神经尾核（trigeminal nucleus caudalis, TNC）区神经胶质细胞中NLRP3炎症小体（Nod-like receptor protein 3 inflammasome）的异常活化与中枢敏化显著相关。基础研究显示，通过调节自噬流（autophagic flux），可靶向清除NLRP3炎症小体的核心组分及其下游分子（NLRP3、ASC、pro-IL-1β），进而有效阻断IL-1β介导的神经炎症级联反应。然而，最新研究发现偏头痛患者和动物模型中均存在自噬功能障碍，这可能是导致偏头痛神经炎症和中枢敏化的重要机制。本文系统梳理了NLRP3/IL-1β信号通路在偏头痛中的研究进展，在此基础上深入探讨自噬功能障碍在发病机制中的潜在病理作用，并首次提出“自噬障碍-神经炎症-中枢敏化”的正反馈环路；旨在为该领域的后续研究及靶向治疗指明方向。

Abstract:

Abstract Migraine is a common chronic neurovascular disorder characterized by recurrent headache attacks that significantly impact patients' quality of life. Accumulating evidence indicates that neuroinflammation plays a critical role in the pathogenesis of migraine, with glial cell activation serving as a central component. Activated glial cells release pro-inflammatory mediators, contributing to neuronal injury. Recent studies have confirmed that abnormal activation of the NLRP3 inflammasome in glial cells within the trigeminal nucleus caudalis (TNC) is closely associated with central sensitization. Basic research has demonstrated that modulating autophagic flux can selectively clear core components and downstream molecules of the NLRP3 inflammasome (e.g., NLRP3, ASC, and pro-IL-1β), thereby effectively inhibiting the IL-1β-mediated neuroinflammatory cascade. However, emerging evidence suggests that impaired autophagic flux occurs in both migraine patients and animal models, which may represent a key mechanism underlying neuroinflammation and central sensitization in migraine. This review systematically summarizes recent advances in the understanding of the NLRP3/IL-1β signaling pathway in migraine, explores the potential pathogenic role of autophagy dysfunction in its pathophysiology, and proposes, for the first time, a positive feedback loop involving “autophagy dysfunction–neuroinflammation–central sensitization.” The aim is to provide new directions for future research and targeted therapeutic strategies in this field.