Ping Yukun, Li Jiyu, Xie Linlin, Zhao Jie, Chen Xuyu, Chen Danni, Wang Yamin, Jiang Chao, Li Xiaobo
Clinical Medical College, Yangzhou University, Yangzhou 225009, China; Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou 225001, China.
Department of Orthopedic Oncology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China.
Brain Res. 2025 Feb 15;1849:149381. doi: 10.1016/j.brainres.2024.149381. Epub 2024 Dec 4.
Ischemic stroke is a leading cause of disability and mortality worldwide, with limited effective treatments. Neuroinflammation plays a crucial role in the progression of ischemic brain injury. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has emerged as a potential regulator of inflammation, but its role and underlying mechanisms in ischemic stroke remain largely unknown.
We investigated the expression profile, functional significance, and molecular pathways of GPNMB in ischemic stroke using a mouse model of middle cerebral artery occlusion (MCAO), transcriptome sequencing, and human serum samples. The effects of GPNMB knockdown on stroke outcomes, neuroinflammation, and neuronal damage were assessed in vivo. Bioinformatic analyses and experimental validation were performed to identify the downstream signaling pathways of GPNMB.
GPNMB was highly upregulated in the ischemic brain, with its expression peaking at 3-7 days post-MCAO. Serum GPNMB levels were elevated in ischemic stroke patients and correlated with stroke severity. GPNMB knockdown exacerbated stroke outcomes, neuroinflammation, and neuronal damage. Mechanistically, GPNMB positively modulated the PI3K/Akt/GSK3β pathway while negatively regulating p38 MAPK, JNK, and ERK activation. GPNMB knockdown enhanced the expression of NF-κB, a master transcriptional regulator of inflammation.
GPNMB is highly upregulated in the ischemic brain and confers neuroprotection against ischemic injury by modulating neuroinflammation via the PI3K/Akt and p38 MAPK signaling pathways.
缺血性中风是全球致残和致死的主要原因之一，有效治疗手段有限。神经炎症在缺血性脑损伤的进展中起关键作用。糖蛋白非转移性黑色素瘤蛋白B（GPNMB）已成为一种潜在的炎症调节因子，但其在缺血性中风中的作用及潜在机制仍 largely 未知。
我们使用大脑中动脉闭塞（MCAO）小鼠模型、转录组测序和人类血清样本，研究了 GPNMB 在缺血性中风中的表达谱、功能意义和分子途径。在体内评估了 GPNMB 敲低对中风结局、神经炎症和神经元损伤的影响。进行了生物信息学分析和实验验证，以确定 GPNMB 的下游信号通路。
GPNMB 在缺血性脑中高度上调，其表达在 MCAO 后 3 - 7 天达到峰值。缺血性中风患者血清 GPNMB 水平升高，且与中风严重程度相关。GPNMB 敲低加剧了中风结局、神经炎症和神经元损伤。机制上，GPNMB 正向调节 PI3K/Akt/GSK3β 途径，同时负向调节 p38 MAPK、JNK 和 ERK 的激活。GPNMB 敲低增强了炎症的主要转录调节因子 NF-κB 的表达。
GPNMB 在缺血性脑中高度上调，并通过 PI3K/Akt 和 p38 MAPK 信号通路调节神经炎症，对缺血性损伤具有神经保护作用。
