Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, SMMU, Shanghai, 200433, China.
Department of Gastroenterology, Changhai Hospital, SMMU, Shanghai, 200433, China.
Adv Sci (Weinh). 2022 Aug;9(24):e2105442. doi: 10.1002/advs.202105442. Epub 2022 Jun 27.
Blood-brain barrier (BBB) impairment is an early prevalent feature of multiple sclerosis (MS), and remains vital for MS progression. Microglial activation precedes BBB disruption and cellular infiltrates in the brain of MS patients. However, little is known about the function of microglia in BBB impairment. Here, microglia acts as an important modulator of BBB integrity in inflammatory demyelination. Microglial depletion profoundly ameliorates BBB impairment in experimental autoimmune encephalomyelitis (EAE). Specifically, miR-126a-5p in microglia is positively correlated with BBB integrity in four types of MS plaques. Mechanistically, microglial deletion of miR-126a-5p exacerbates BBB leakage and EAE severity. The protective effect of miR-126a-5p is mimicked and restored by specific inhibition of MMP9 in microglia. Importantly, Auranofin, an FDA-approved drug, is identified to protect BBB integrity and mitigate EAE progression via a microglial miR-126a-5p dependent mechanism. Taken together, microglia can be manipulated to protect BBB integrity and ameliorate inflammatory demyelination. Targeting microglia to regulate BBB permeability merits consideration in therapeutic interventions in MS.
血脑屏障（BBB）损伤是多发性硬化症（MS）的早期普遍特征，对 MS 进展仍然至关重要。在 MS 患者的大脑中，小胶质细胞的激活先于 BBB 破坏和细胞浸润。然而，关于小胶质细胞在 BBB 损伤中的作用知之甚少。在这里，小胶质细胞作为炎症性脱髓鞘中 BBB 完整性的重要调节剂。实验性自身免疫性脑脊髓炎（EAE）中小胶质细胞的耗竭可显著改善 BBB 损伤。具体而言，四种 MS 斑块中小胶质细胞中的 miR-126a-5p 与 BBB 完整性呈正相关。在机制上，小胶质细胞中 miR-126a-5p 的缺失会加剧 BBB 渗漏和 EAE 严重程度。特异性抑制小胶质细胞中的 MMP9 可模拟和恢复 miR-126a-5p 的保护作用。重要的是，金诺芬，一种 FDA 批准的药物，通过小胶质细胞依赖的 miR-126a-5p 机制被鉴定为保护 BBB 完整性并减轻 EAE 进展。总之，小胶质细胞可被操纵以保护 BBB 完整性并减轻炎症性脱髓鞘。靶向小胶质细胞调节 BBB 通透性值得在 MS 的治疗干预中考虑。
