Department of Neurology, The Second Affiliated Hospital of Zhejiang, University School of Medicine, Hangzhou, China.
Department of Neurology, Changxing Hospital, Second Affiliated Hospital of Medical College of Zhejiang University, Huzhou, China.
Front Immunol. 2020 Sep 4;11:1934. doi: 10.3389/fimmu.2020.01934. eCollection 2020.
Long non-coding RNA (lncRNA) is pivotal for multiple sclerosis (MS), but the potential mechanism of lncRNA PVT1 in MS animal model, experimental autoimmune encephalomyelitis (EAE) still remains unclear. In this study, macrophages were firstly isolated and induced to polarize into M2 macrophages. M2 macrophage-derived exosomes (M2-exos) were extracted and identified, and EAE mouse model was established and treated with M2-exos. The effect of M2-exos on EAE mice was evaluated by clinical scores. The proportion of Treg and Th17 cells in spinal cord cells and splenocytes, and levels of inflammatory factors were measured. The targeting relationships among PVT1, miR-21-5p, and SOCS5 were verified. The expression of JAKs/STAT3 pathway-related proteins was measured. After M2-exo treatment, the clinical score of EAE mice decreased, and demyelination and inflammatory infiltration improved; Th17 cells decreased, Treg cells increased, and the levels of inflammatory factors decreased significantly. SOCS5 and PVT1 were downregulated and miR-21-5p was upregulated in EAE mice. PVT1 could sponge miR-21-5p to regulate SOCS5. SOCS5 alleviated EAE symptoms by repressing the JAKs/STAT3 pathway. Together, M2-exos-carried lncRNA PVT1 sponged miR-21-5p to upregulate SOCS5 and inactivate the JAKs/STAT3 pathway, thus reducing inflammation and protecting EAE mice. This study may offer novel treatments for MS.
长链非编码 RNA（lncRNA）在多发性硬化症（MS）中起着关键作用，但 lncRNA PVT1 在 MS 动物模型、实验性自身免疫性脑脊髓炎（EAE）中的潜在机制仍不清楚。在这项研究中，首先分离巨噬细胞并诱导其极化为 M2 巨噬细胞。提取并鉴定 M2 巨噬细胞衍生的外体（M2-exos），并建立 EAE 小鼠模型并用 M2-exos 进行处理。通过临床评分评估 M2-exos 对 EAE 小鼠的影响。测量脊髓细胞和脾细胞中 Treg 和 Th17 细胞的比例以及炎症因子的水平。验证 PVT1、miR-21-5p 和 SOCS5 之间的靶向关系。测量 JAKs/STAT3 通路相关蛋白的表达。经 M2-exo 处理后，EAE 小鼠的临床评分降低，脱髓鞘和炎症浸润改善；Th17 细胞减少，Treg 细胞增加，炎症因子水平显著降低。EAE 小鼠中 SOCS5 和 PVT1 下调，miR-21-5p 上调。PVT1 可以通过海绵 miR-21-5p 来调节 SOCS5。SOCS5 通过抑制 JAKs/STAT3 通路缓解 EAE 症状。总之，M2-exos 携带的 lncRNA PVT1 海绵 miR-21-5p 上调 SOCS5 并使 JAKs/STAT3 通路失活，从而减少炎症并保护 EAE 小鼠。这项研究可为 MS 提供新的治疗方法。
