School of Clinical Medicine, Guizhou Medical University, Guiyang, China.
Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, China.
Neuropeptides. 2024 Aug;106:102436. doi: 10.1016/j.npep.2024.102436. Epub 2024 May 8.
Microglial phagocytosis of myelin debris is a crucial process for promoting myelin regeneration in conditions such as multiple sclerosis (MS). Vacuolar-ATPase B2 (V-ATPase B2) has been implicated in various cellular processes, but its role in microglial phagocytosis and its potential impact on MS-related responses remain unclear. In this study, we employed BV-2 murine microglial cells to investigate the influence of V-ATPase B2 on the phagocytosis of myelin debris by microglia. The results revealed that V-ATPase B2 expression increased in response to myelin debris exposure. Overexpression of V-ATPase B2 significantly enhanced BV-2 phagocytosis of myelin debris. Additionally, V-ATPase B2 overexpression shifted microglial polarization towards an anti-inflammatory M2 phenotype, coupled with decreased lysosomal pH and enhanced lysosome degradation capacity. Moreover, endoplasmic reticulum (ER) stress inhibitor, 4-PBA, reversed the effects of V-ATPase B2 silencing on ER stress, M2 polarization, and lysosomal degradation of BV-2 cells. The MAPK pathway was inhibited upon V-ATPase B2 overexpression, contributing to heightened myelin debris clearance by BV-2 cells. Notably, MAPK pathway inhibition partially attenuated the inhibitory effects of V-ATPase B2 knockdown on myelin debris clearance. In conclusion, our findings reveal a pivotal role for V-ATPase B2 in promoting microglial phagocytosis of myelin debris by regulating microglial polarization and lysosomal function via the MAPK signaling pathway, suggesting that targeting V-ATPase B2 may hold therapeutic potential for enhancing myelin debris clearance and modulating microglial responses in MS and related neuroinflammatory disorders.
小胶质细胞吞噬髓鞘碎片是促进多发性硬化症（MS）等情况下髓鞘再生的关键过程。液泡型 ATP 酶 B2（V-ATPase B2）参与多种细胞过程，但它在小胶质细胞吞噬中的作用及其对 MS 相关反应的潜在影响尚不清楚。在这项研究中，我们使用 BV-2 鼠小胶质细胞来研究 V-ATPase B2 对小胶质细胞吞噬髓鞘碎片的影响。结果表明，V-ATPase B2 的表达在暴露于髓鞘碎片后增加。V-ATPase B2 的过表达显著增强了 BV-2 对髓鞘碎片的吞噬作用。此外，V-ATPase B2 的过表达将小胶质细胞极化向抗炎 M2 表型转变，同时降低溶酶体 pH 值并增强溶酶体降解能力。此外，内质网（ER）应激抑制剂 4-PBA 逆转了 V-ATPase B2 沉默对 ER 应激、M2 极化和 BV-2 细胞溶酶体降解的影响。V-ATPase B2 的过表达抑制了 MAPK 途径，促进了 BV-2 细胞对髓鞘碎片的清除。值得注意的是，MAPK 途径的抑制部分减弱了 V-ATPase B2 敲低对髓鞘碎片清除的抑制作用。总之，我们的研究结果表明，V-ATPase B2 通过调节 MAPK 信号通路促进小胶质细胞吞噬髓鞘碎片，在调节小胶质细胞极化和溶酶体功能方面发挥着关键作用，提示靶向 V-ATPase B2 可能具有增强髓鞘碎片清除和调节 MS 及相关神经炎症性疾病中小胶质细胞反应的治疗潜力。
