As a chronic inflammatory disorder of the central nervous system (CNS) (Koch-Henriksen and Sorensen, 2010), multiple sclerosis (MS) is characterized by primary demyelination with a variable degree of axonal loss (Ji et al., 2013). As the most frequent cause of non-traumatic disability in young and middle-aged adults (Inglese and Bester, 2010), MS commonly emerges in people between the ages of 20 and 40 and shows a higher incidence rate in women than in men (Giannopapas et al., 2023). Currently, the immunomodulatory treatments for MS mainly target CNS inflammation; however, there is still a lack of therapies that can regenerate myelin and halt disease progression (Lassmann et al., 2007). Hence, there is a need for better knowledge of the mechanisms underlying remyelination to develop long-term regenerative therapeutic options for patients with MS.

In MS, demyelination causes myelin debris accumulation and axonal damage, leading to neurological disability (Sen et al., 2022). Efficient removal of myelin debris by phagocytic cells is necessary for limiting inflammation, promoting remyelination, and neural repair (Ruckh et al., 2012). Microglia, resident immune cells of the CNS (Kettenmann et al., 2011), play a pivotal role in myelin debris clearance and subsequent neural repair (Quan et al., 2022). A great number of studies have proven the role of microglia in myelin debris clearance in demyelination diseases, including MS (Cignarella et al., 2020; Sen et al., 2022; Shen et al., 2022). Hence, fostering microglial phagocytosis of myelin debris could offer a promising avenue for MS treatment.

Vacuolar-type ATPase (V-ATPase) is a multi-subunit enzyme complex involved in the regulation of intracellular pH and vesicular trafficking (Katara et al., 2018). V-ATPase has been demonstrated to be a universal regulator of LC3-associated phagocytosis (Hooper et al., 2022). Also, a previous study has shown that V-ATPase is involved in the regulation of microglial phagocytosis in vivo (Peri and Nusslein-Volhard, 2008), indicating that V-ATPase might play a critical role in microglial-mediated neuronal degeneration. Recently, V-ATPase B2, a V-ATPase subunit, has been proven to exert a neuroprotective role against fluoride-induced developmental neurotoxicity by promoting lysosomal acidification and degradation (Han et al., 2022). In addition, V-ATPase B2-overexpressing macrophages exhibited lower lysosomal pH and increased lysosomal activity (Lee et al., 2022), indicating its role in regulating the lysosomal functions of phagocytes. Therefore, V-ATPase B2 might promote microglial phagocytosis of myelin debris, thereby alleviating MS.

In this study, we aimed to elucidate the precise mechanisms by which V-ATPase B2 influences microglial phagocytosis of myelin debris and how its interaction with the MAPK signaling pathway. By unraveling the molecular underpinnings of V-ATPase B2-mediated microglial phagocytosis, we seek to uncover potential therapeutic targets for promoting effective myelin debris clearance and fostering neurorepair in the context of MS.