V-ATPase B2 promotes microglial phagocytosis of myelin debris by inactivating the MAPK signaling pathway

IF 2.5 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Neuropeptides Pub Date : 2024-05-08 DOI:10.1016/j.npep.2024.102436
Yao Li , Yuhan Dai , Lan Chu
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Abstract

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.

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V-ATPase B2 通过使 MAPK 信号通路失活来促进小胶质细胞吞噬髓鞘碎片
在多发性硬化症(MS)等疾病中,小胶质细胞吞噬髓鞘碎片是促进髓鞘再生的关键过程。空泡ATP酶B2(V-ATP酶B2)与多种细胞过程有关,但它在小胶质细胞吞噬中的作用及其对多发性硬化症相关反应的潜在影响仍不清楚。在本研究中,我们利用 BV-2 小鼠小胶质细胞研究了 V-ATPase B2 对小胶质细胞吞噬髓鞘碎片的影响。结果发现,V-ATPase B2的表达随着髓鞘碎片的暴露而增加。V-ATPase B2的过表达能显著增强BV-2对髓鞘碎片的吞噬能力。此外,V-ATPase B2 的过表达使小胶质细胞极化转向抗炎 M2 表型,同时溶酶体 pH 值降低,溶酶体降解能力增强。此外,内质网(ER)应激抑制剂4-PBA能逆转V-ATPase B2沉默对BV-2细胞ER应激、M2极化和溶酶体降解的影响。V-ATPase B2过表达后,MAPK通路受到抑制,从而促进了BV-2细胞对髓鞘碎片的清除。值得注意的是,MAPK通路抑制可部分减弱V-ATPase B2敲除对髓鞘碎片清除的抑制作用。总之,我们的研究结果揭示了 V-ATPase B2 通过 MAPK 信号通路调节小胶质细胞的极化和溶酶体功能,从而在促进小胶质细胞吞噬髓鞘碎片的过程中发挥了关键作用。
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来源期刊
Neuropeptides
Neuropeptides 医学-内分泌学与代谢
CiteScore
5.40
自引率
6.90%
发文量
55
审稿时长
>12 weeks
期刊介绍: The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.
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