Caveolin-1 negatively regulates the calcitonin receptor-like receptor and neuroinflammation in a female mouse model of migraine.

IF 9.3 1区医学 Q1 IMMUNOLOGY

Journal of Neuroinflammation Pub Date : 2025-05-21 DOI:10.1186/s12974-025-03466-8

Yanjie Zhou, Wu Chen, Yu Zhang, Liu Yang, Fu Lu, Wen Yan, Qingfang Xie, Ying Huang, Wanbin Huang, Lintao Wang, Ziming Zeng, Zheman Xiao

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引用次数: 0

Abstract

Background: Caveolin-1 (CAV1), a scaffolding protein critical for caveolae formation, regulates G-protein-coupled receptor (GPCR) signaling via caveolae-mediated endocytosis. The calcitonin receptor-like receptor (CLR), a GPCR and core subunit of the calcitonin gene-related peptide (CGRP) receptor, is a therapeutic target for migraine. However, the role of CAV1 in CLR regulation and migraine remains unclear.

Methods: A migraine model was established in female mice via dural inflammatory soup (IS) application. Migraine-like behaviors were assessed using Von Frey filament, spontaneous pain behavior counts, light/dark box, and acetone test. CAV1 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. Methyl-β-cyclodextrin (MβCD) was used to inhibit caveolae-mediated endocytosis. The molecular mechanism of CAV1 on CLR and neuroinflammation was investigated using biochemistry, multiplex immunohistochemistry staining, internalization assay, and co-immunoprecipitation.

Results: Repeated IS stimulation elevated CLR expression and internalization in the trigeminal nucleus caudalis (TNC), concurrently activating ERK/CREB signaling, promoting microglial activation, and increasing inflammatory cytokines (TNFα, IL-1β). CAV1 directly interacted with CLR, promoting its degradation. CAV1 knockdown in the TNC exacerbated migraine pathology, characterized by CLR accumulation, enhanced ERK/CREB phosphorylation, and amplified neuroinflammation. Conversely, CAV1 overexpression or MβCD-mediated caveolae disruption normalized CLR levels, reduced signaling hyperactivity, and reversed nociceptive behaviors.

Conclusion: CAV1 negatively regulates CLR stability, suppressing ERK/CREB signaling and microglial inflammation in a preclinical female migraine model. These findings suggest that CAV1 contributes to migraine-related hyperalgesia and may represent a novel therapeutic target for migraine treatment.

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Caveolin-1负向调节女性偏头痛小鼠降钙素受体样受体和神经炎症。

背景：Caveolin-1 （CAV1）是一种对小窝形成至关重要的支架蛋白，通过小窝介导的内吞作用调节g蛋白偶联受体（GPCR）信号传导。降钙素受体样受体（CLR）是降钙素基因相关肽（CGRP）受体的GPCR和核心亚基，是偏头痛的治疗靶点。然而，CAV1在CLR调控和偏头痛中的作用尚不清楚。方法：应用硬脑膜炎汤（IS）建立雌鼠偏头痛模型。采用Von Frey纤维、自发疼痛行为计数、明暗盒和丙酮试验评估偏头痛样行为。CAV1通过慢病毒过表达，小干扰RNA （siRNA）技术下调。用甲基β-环糊精（m -β cd）抑制小泡介导的内吞作用。采用生物化学、多重免疫组织化学染色、内化实验和共免疫沉淀等方法研究CAV1对CLR和神经炎症的分子机制。结果：反复IS刺激提高三叉神经尾核（TNC） CLR的表达和内化，同时激活ERK/CREB信号，促进小胶质细胞活化，增加炎症因子（TNFα, IL-1β）。CAV1直接与CLR相互作用，促进其降解。TNC中CAV1的下调加重了偏头痛的病理，其特征是CLR积累、ERK/CREB磷酸化增强和神经炎症放大。相反，CAV1过表达或m β cd介导的小泡破坏使CLR水平正常化，减少信号过度活跃，逆转伤害性行为。结论：在临床前女性偏头痛模型中，CAV1负调控CLR稳定性，抑制ERK/CREB信号和小胶质细胞炎症。这些发现表明，CAV1与偏头痛相关的痛觉过敏有关，可能是偏头痛治疗的一个新的治疗靶点。

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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.