GPNMB Ameliorates Neuroinflammation Via the Modulation of AMPK/NFκB Signaling Pathway After SAH in Mice.
GPNMB Ameliorates Neuroinflammation Via the Modulation of AMPK/NFκB Signaling Pathway After SAH in Mice.
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DOI：
10.1007/s11481-023-10087-6
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发表时间：
2023-12
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糖蛋白非转移性黑色素瘤蛋白B（GPNMB）的名称来自于在非转移性黑色素瘤细胞系中的首次发现。后来的研究发现，GPNMB广泛表达于人体的各种组织和细胞中，在神经组织、上皮组织、骨组织和单核-巨噬细胞系统中表达最为丰富。GPNMB已被证明在多种神经系统疾病中具有抗炎作用，然而，尚未报道其在蛛网膜下腔出血（SAH）中的作用。采用雄性CD-1小鼠，采用动脉穿刺法建立SAH模型。SAH后1h侧脑室注射外源性重组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对结局的影响。选择性AMPK抑制剂Dorsomorphin被引入GPNMB的下游信号通路研究。此外，蛋白质印迹、免疫荧光染色和ELISA用于确认信号传导。SAH后，GPNMB表达显著增加，作为炎症反应的结果。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能减轻SAH小鼠脑水肿，恢复血脑屏障的完整性，改善SAH小鼠的神经功能。GPNMB处理后p-AMPK表达增强，p-NFκB、IL-1β、IL-6和TNF-α表达减弱; GPNMB与AMPK抑制剂联合应用可降低p-AMPK表达强度，逆转p-NFκB和上述炎性细胞因子的表达。GPNMB可能通过AMPK/NFκB信号通路减轻脑水肿和神经炎症，保护脑B，改善神经功能。 在线版本包含补充材料，可通过10.1007/s11481-023-10087-6获得。
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. The online version contains supplementary material available at 10.1007/s11481-023-10087-6.