Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, China.
Department of Translational Medicine Research Center, Guizhou Medical University, Guiyang, China.
Oxid Med Cell Longev. 2022 Feb 16;2022:8603427. doi: 10.1155/2022/8603427. eCollection 2022.
Ischemic stroke is a common disease of the central nervous system, and ischemic brain injury (IBI) is its main manifestation. Recently, extracellular vesicles (EVs) have been strongly related to the diagnosis and treatment of IBI. However, the underlying mechanism of their effects remains enigmatic. In the present study, we aimed to study how miR-155-5p plays a role in choroid plexus epithelial (CPE) cell-derived EVs in IBI pathology. We found that miR-155-5p expression was enriched in CPE cell-derived EVs, which were subsequently internalized by neurons, enabling the delivery of miR-155-5p into neurons. An inducible oxygen and glucose deprivation and reoxygenation (OGD/R) cell model was developed to mimic ischemic neuronal injury . miR-155-5p overexpression led to reduced neuron viability, promoted apoptosis, elevated autophagic proteins' expression, and activated NLR family pyrin domain-containing 3- (NLRP3-) related inflammasomes, thereby aggravating OGD-induced neuronal injury. A dual-luciferase reporter assay exhibited that miR-155-5p could inhibit the Ras homolog enriched in brain (Rheb) expression, a mechanism critical for miR-155-5p-mediated neuronal injury. Furthermore, a mouse IBI model was developed using the transient middle cerebral artery occlusion (tMCAO) method. Animal experiments verified that miR-155p delivery via CPE cell-derived EVs aggravated IBI by suppressing Rheb expression. In conclusion, miR-155-5p in CPE-derived EVs can aggravate IBI pathology by suppressing Rheb expression and promoting NLRP3-mediated inflammasomes, suggesting its role as a potential therapeutic target in IBI.
缺血性脑卒中是一种常见的中枢神经系统疾病，其主要表现为缺血性脑损伤（IBI）。最近，细胞外囊泡（EVs）与 IBI 的诊断和治疗密切相关。然而，其作用的潜在机制仍然是个谜。在本研究中，我们旨在研究 miR-155-5p 在脉络丛上皮（CPE）细胞衍生的 EVs 中在 IBI 发病机制中的作用。我们发现 miR-155-5p 在 CPE 细胞衍生的 EVs 中表达丰富，随后被神经元内化，使 miR-155-5p 能够递送到神经元中。我们建立了诱导性氧和葡萄糖剥夺及再氧合（OGD/R）细胞模型，以模拟缺血性神经元损伤。miR-155-5p 的过表达导致神经元活力降低，促进细胞凋亡，增加自噬蛋白的表达，并激活 NOD 样受体家族含pyrin 结构域蛋白 3（NLRP3）相关的炎性小体，从而加重 OGD 诱导的神经元损伤。双荧光素酶报告基因实验表明，miR-155-5p 可以抑制 Ras 同源物富集在脑（Rheb）的表达，这是 miR-155-5p 介导神经元损伤的关键机制。此外，我们使用短暂性大脑中动脉闭塞（tMCAO）方法建立了小鼠 IBI 模型。动物实验验证了通过 CPE 细胞衍生的 EVs 递送 miR-155p 通过抑制 Rheb 表达加重 IBI。总之，CPE 衍生的 EVs 中的 miR-155-5p 通过抑制 Rheb 表达和促进 NLRP3 介导的炎性小体加重 IBI 病理，表明其作为 IBI 潜在治疗靶点的作用。
