Microglia Regulate Blood-Brain Barrier Integrity via MiR-126a-5p/MMP9 Axis during Inflammatory Demyelination.
Microglia Regulate Blood-Brain Barrier Integrity via MiR-126a-5p/MMP9 Axis during Inflammatory Demyelination.
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小胶质细胞在炎症脱髓鞘过程中通过 MiR-126a-5p/MMP9 轴调节血脑屏障完整性。
DOI：
10.1002/advs.202105442
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发表时间：
2022-08
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血脑屏障（BBB）损伤是多发性硬化（MS）的早期普遍特征，并且对于MS进展仍然至关重要。MS患者脑中小胶质细胞活化先于BBB破坏和细胞浸润。然而，小胶质细胞在血脑屏障损伤中的功能知之甚少。在这里，小胶质细胞作为一个重要的调制器的血脑屏障的完整性，炎症脱髓鞘。实验性自身免疫性脑脊髓炎（EAE）中小胶质细胞耗竭可显著改善BBB损伤。具体而言，小胶质细胞中的miR-126 a-5 p与四种类型的MS斑块中的BBB完整性正相关。从机制上讲，miR-126 a-5 p的小胶质细胞缺失加剧了BBB渗漏和EAE的严重程度。miR-126 a-5 p的保护作用通过特异性抑制小胶质细胞中的MMP 9来模拟和恢复。重要的是，FDA批准的药物Auranofin被鉴定为通过小胶质细胞miR-126 a-5 p依赖性机制保护BBB完整性并减轻EAE进展。总之，可以操纵小胶质细胞以保护BBB完整性并改善炎性脱髓鞘。靶向小胶质细胞调节血脑屏障通透性值得考虑在MS的治疗干预。小胶质细胞耗竭减轻血脑屏障（BBB）的破坏在炎症脱髓鞘。在四种类型的多发性硬化斑块中，小胶质细胞中的miR-126 a-5 p与BBB完整性呈正相关。小胶质细胞通过MiR-126 a-5 p/MMP 9轴改善BBB破坏。Auranofin升高miR-126 a-5 p以保持BBB完整性并缓解实验性自身免疫性脑脊髓炎进展。
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. Microglial depletion mitigates blood–brain barrier (BBB) disruption during inflammatory demyelination. MiR‐126a‐5p in microglia is positively correlated with BBB integrity in four types of multiple sclerosis plaques. Microglia ameliorates BBB destruction via MiR‐126a‐5p/MMP9 axis. Auranofin elevates miR‐126a‐5p to preserve BBB integrity and alleviate experimental autoimmune encephalomyelitis progression.