International immunopharmacology · 2025
MYCN-mediated pyroptosis and inflammation in the molecular mechanism of MicroRNA-202-3P promote functional recovery in spinal cord injury.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Fang Jing, Huang Ke, Zhang Guodong, Shi Bowen, Bi Haidi, Shuai Lang
Аннотация
BACKGROUND: Spinal cord injury (SCI), which induces severe neurological dysfunction, triggers secondary damage driven primarily by neuroinflammation and pyroptosis. Although microRNA-202-3P (miR-202-3p) is recognized for its regulatory role in inflammatory pathways, its specific involvement in SCI and the underlying mechanisms remain poorly understood.
METHODS: A rat SCI model was induced via T10 spinal cord compression, followed by intravenous miR-202-3p administration. Functional recovery was evaluated through the Basso-Beattie-Bresnahan (BBB) score and footprint test. Histopathological changes were evaluated through Hematoxylin and eosin (H&E) staining and Luxol Fast Blue (LFB) Staining. Ultrastructural analysis was performed by transmission electron microscopy (TEM). Immunofluorescence, Western blotting, qPCR, and dual-luciferase assays were used to examine microglial polarization, pyroptosis, and molecular signaling. In vitro, LPS + ATP-stimulated BV-2 microglia were employed to further validate miR-202-3p's effects. Additionally, a co-culture model of BV-2 microglia and VSC4.1 motor neurons was established to assess the neuroprotective effects of miR-202-3p via conditioned media transfer.
RESULTS: miR-202-3p treatment significantly improved motor function and bladder control after SCI. It led to M2 microglial polarization, suppression of NLRP3 inflammasome activation, and a reduction in pyroptosis markers. TEM analysis indicated preserved endoplasmic reticulum and mitochondrial integrity in miRNA group, suggesting inhibition of pyroptosis. Additionally, enhanced neuronal survival, remyelination, and structural repair were observed. In the co-culture model, miR-202-3p-treated microglial conditioned media significantly enhanced neuronal survival and reduced apoptosis. Mechanistically, miR-202-3p directly targeted and downregulated MYCN, inhibiting the TLR4/NF-κB/NLRP3 pathway. MYCN overexpression counteracted the inhibitory effects of miR-202-3p on inflammation and pyroptosis.
CONCLUSIONS: miR-202-3p mitigates SCI by inhibiting neuroinflammation and pyroptosis via MYCN-mediated suppression of the TLR4/NF-κB/NLRP3 signaling pathway. The findings suggest miR-202-3p as a promising candidate for therapeutic intervention, offering dual benefits of reducing secondary injury and promoting functional restoration post-SCI.
METHODS: A rat SCI model was induced via T10 spinal cord compression, followed by intravenous miR-202-3p administration. Functional recovery was evaluated through the Basso-Beattie-Bresnahan (BBB) score and footprint test. Histopathological changes were evaluated through Hematoxylin and eosin (H&E) staining and Luxol Fast Blue (LFB) Staining. Ultrastructural analysis was performed by transmission electron microscopy (TEM). Immunofluorescence, Western blotting, qPCR, and dual-luciferase assays were used to examine microglial polarization, pyroptosis, and molecular signaling. In vitro, LPS + ATP-stimulated BV-2 microglia were employed to further validate miR-202-3p's effects. Additionally, a co-culture model of BV-2 microglia and VSC4.1 motor neurons was established to assess the neuroprotective effects of miR-202-3p via conditioned media transfer.
RESULTS: miR-202-3p treatment significantly improved motor function and bladder control after SCI. It led to M2 microglial polarization, suppression of NLRP3 inflammasome activation, and a reduction in pyroptosis markers. TEM analysis indicated preserved endoplasmic reticulum and mitochondrial integrity in miRNA group, suggesting inhibition of pyroptosis. Additionally, enhanced neuronal survival, remyelination, and structural repair were observed. In the co-culture model, miR-202-3p-treated microglial conditioned media significantly enhanced neuronal survival and reduced apoptosis. Mechanistically, miR-202-3p directly targeted and downregulated MYCN, inhibiting the TLR4/NF-κB/NLRP3 pathway. MYCN overexpression counteracted the inhibitory effects of miR-202-3p on inflammation and pyroptosis.
CONCLUSIONS: miR-202-3p mitigates SCI by inhibiting neuroinflammation and pyroptosis via MYCN-mediated suppression of the TLR4/NF-κB/NLRP3 signaling pathway. The findings suggest miR-202-3p as a promising candidate for therapeutic intervention, offering dual benefits of reducing secondary injury and promoting functional restoration post-SCI.