骨髓间充质干细胞来源的细胞外囊泡通过 miR-183-5p/PDCD4/NLRP3 通路减轻糖尿病性脑出血后的神经炎症。
Extracellular vesicles derived from bone marrow mesenchymal stem cells alleviate neuroinflammation after diabetic intracerebral hemorrhage via the miR-183-5p/PDCD4/NLRP3 pathway.
机构信息
Department of Orthopedics, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Bengbu, 233004, Anhui, People's Republic of China.
Anhui Key Laboratory of Tissue Transplantation, The First Affiliated Hospital of Bengbu Medical College, Anhui, 233004, People's Republic of China.
出版信息
J Endocrinol Invest. 2021 Dec;44(12):2685-2698. doi: 10.1007/s40618-021-01583-8. Epub 2021 May 23.
OBJECTIVES
Intracerebral hemorrhage (ICH) induced by diabetes results in further brain injury and nerve cell death. Bone marrow mesenchymal stem cell (BMSC) transplantation contributes to attenuating neurological deficits after ICH. This study investigated the mechanism of extracellular vesicles (EVs) derived from BMSCs in reducing neuroinflammation after diabetic ICH.
METHODS
BMSC-EVs were isolated and identified. The rat model of db/db-ICH was established and the model rats were administered with EVs. miR-183-5p expression in brain tissues of db/db-ICH rats was detected. The brain injury of db/db-ICH rats was evaluated by measuring neurobehavioral score, brain water content and inflammatory factors. BV2 cells were cultured in vitro to establish high-glucose (HG)-Hemin-BV2 cell model. The levels of reactive oxygen species (ROS) and inflammatory factors in BV2 cells were measured, and BV2 cell viability and apoptosis were assessed. The targeting relationship between miR-183-5p and PDCD4 was predicted and verified. The activation of PDCD4/NLRP3 pathway in rat brain tissues and BV2 cells was detected.
RESULTS
miR-183-5p expression was reduced in db/db-ICH rats brain tissues. BMSC-EVs ameliorated cranial nerve function, decreased brain water content and repressed inflammatory response by carrying miR-183-5p. BMSC-EVs mitigated HG-Hemin-BV2 cell injury, reduced ROS level and suppressed inflammatory response. miR-183-5p targeted PDCD4. PDCD4 promoted BV2 cell inflammation by activating the NLRP3 pathway. BMSC-EVs inhibited HG-Hemin-BV2 cell inflammation through the miR-183-5p/PDCD4/NLRP3 pathway, and inhibition of miR-183-5p reversed the protective effect of EVs.
CONCLUSION
BMSC-EVs carried miR-183-5p into db/db-ICH rat brain tissues and repressed the NLRP3 pathway by targeting PDCD4, thus alleviating neuroinflammation after diabetic ICH.
目的
糖尿病引起的脑出血（ICH）导致进一步的脑损伤和神经细胞死亡。骨髓间充质干细胞（BMSC）移植有助于减轻 ICH 后的神经功能缺损。本研究探讨了源自 BMSC 的细胞外囊泡（EVs）在减轻糖尿病 ICH 后神经炎症中的机制。
方法
分离并鉴定 BMSC-EVs。建立 db/db-ICH 大鼠模型，并给予 EVs。检测 db/db-ICH 大鼠脑组织中 miR-183-5p 的表达。通过测量神经行为评分、脑含水量和炎症因子来评估 db/db-ICH 大鼠的脑损伤。体外培养 BV2 细胞建立高糖（HG）-血晶素-BV2 细胞模型。测量 BV2 细胞中活性氧（ROS）和炎症因子的水平，并评估 BV2 细胞活力和凋亡。预测并验证 miR-183-5p 与 PDCD4 的靶向关系。检测大鼠脑组织和 BV2 细胞中 PDCD4/NLRP3 通路的激活情况。
结果
db/db-ICH 大鼠脑组织中 miR-183-5p 的表达降低。BMSC-EVs 通过携带 miR-183-5p 改善颅神经功能，降低脑含水量，抑制炎症反应。BMSC-EVs 减轻 HG-血晶素-BV2 细胞损伤，降低 ROS 水平，抑制炎症反应。miR-183-5p 靶向 PDCD4。PDCD4 通过激活 NLRP3 通路促进 BV2 细胞炎症。BMSC-EVs 通过 miR-183-5p/PDCD4/NLRP3 通路抑制 HG-血晶素-BV2 细胞炎症，抑制 miR-183-5p 可逆转 EVs 的保护作用。
结论
BMSC-EVs 将 miR-183-5p 带入 db/db-ICH 大鼠脑组织，并通过靶向 PDCD4 抑制 NLRP3 通路，从而减轻糖尿病 ICH 后的神经炎症。
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