Glycoprotein non-metastatic melanoma protein B (GPNMB) got its name from the first discovery in a cell line of non-metastatic melanoma. Later studies found that GPNMB is widely expressed in various tissues and cells of the human body, most abundant in neural tissue, epithelial tissue, bone tissue, and monocyte-macrophage system. GPNMB has been shown to have anti-inflammatory effects in a variety of neurological diseases, however, it has not been reported in subarachnoid hemorrhage (SAH). Male CD-1 mice were used and intra-arterial puncture method was applied to establish the SAH model. Exogenous recombinant GPNMB (rGPNMB) was injected intracerebroventricularly 1 h after SAH. SAH grading, brain edema and blood–brain barrier (BBB) integrity were quantified, and neurobehavioral tests were performed to evaluate the effect of GPNMB on the outcome. Dorsomorphin, the selective inhibitor on AMPK was introduced to study the downstream signaling through which the GPNMB works. Furthermore, western blot, immunofluorescence staining and ELISA were utilized to confirm the signaling. After SAH, GPNMB expression increased significantly as a result of the inflammatory response. GPNMB was expressed extensively in mouse microglia, astrocytes and neurons. The administration of rGPNMB could alleviate brain edema, restore BBB integrity and improve the neurological outcome of mice with SAH. GPNMB treatment significantly magnified the expression of p-AMPK while p-NFκB, IL-1β, IL-6 and TNF-α were suppressed; in the meantime, the combined administration of GPNMB and AMPK inhibitor could decrease the intensity of p-AMPK and reverse the quantity of p-NFκB and the above inflammatory cytokines. GPNMB has the potential of ameliorating the brain edema and neuroinflammation, protecting the BBB and improving the neurological outcome, possibly via the AMPK/NFκB signaling pathway.

Graphical Abstract

中文翻译：

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GPNMB 通过调节 AMPK/NFκB 信号通路改善小鼠 SAH 后的神经炎症

糖蛋白非转移性黑色素瘤蛋白 B (GPNMB) 因首次在非转移性黑色素瘤细胞系中发现而得名。后来的研究发现GPNMB广泛表达于人体多种组织和细胞中，以神经组织、上皮组织、骨组织、单核巨噬细胞系统最为丰富。GPNMB 已被证明对多种神经系统疾病具有抗炎作用，但在蛛网膜下腔出血 (SAH) 中尚未有报道。采用雄性CD-1小鼠，采用动脉穿刺法建立SAH模型。SAH后1小时脑室内注射外源重组GPNMB（rGPNMB）。对 SAH 分级、脑水肿和血脑屏障 (BBB) 完整性进行量化，并进行神经行为测试以评估 GPNMB 对结果的影响。Dorsomorphin（AMPK 的选择性抑制剂）被引入来研究 GPNMB 发挥作用的下游信号传导。此外，利用蛋白质印迹、免疫荧光染色和 ELISA 来确认信号传导。SAH 后，炎症反应导致 GPNMB 表达显着增加。GPNMB 在小鼠小胶质细胞、星形胶质细胞和神经元中广泛表达。rGPNMB 的给药可以减轻 SAH 小鼠的脑水肿，恢复 BBB 完整性并改善神经系统结果。GPNMB处理显着放大p-AMPK的表达，同时抑制p-NFκB、IL-1β、IL-6和TNF-α的表达；同时，GPNMB和AMPK抑制剂联合给药可降低p-AMPK的强度并逆转p-NFκB和上述炎症细胞因子的数量。GPNMB 可能通过 AMPK/NFκB 信号通路改善脑水肿和神经炎症、保护 BBB 并改善神经系统结果。

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