STING signaling in vestibular macrophages underlies Ménière’s disease pathogenesis

Ménière’s disease (MD) is a disabling inner-ear disorder. Although the key pathologic alteration of MD is characterized as endolymphatic hydrops (EH), the underlying pathogenic mechanism remains unclear, and no definitive curative treatments are available. Emerging evidence implicates oxidative stress and innate immunity as key contributors to MD pathogenesis. Human vestibular end organs were collected to characterize the reactive oxygen species (ROS) levels and the STING signaling activation, findings that were further corroborated in an LPS-induced EH mouse model. Transfection and transwell co-culture were performed to investigate the feedback loop between sensory epithelial cells and macrophages in vitro. Molecular biology experiments were performed to elucidate the underlying regulatory mechanisms. Additionally, STING and CUL4B deficiency mice were used to explore potential therapeutic targets in vivo. The oxidative stress, cytoplasmic dsDNA leakage, and STING activation were elevated in both MD patients and LPS-induced EH mouse model. The dsDNA released from ROS-damaged hair cells activates STING in vestibular macrophages. STING-specific knockout in macrophages alleviates EH, audio-vestibular dysfunction, and interferon-stimulated genes expression in mouse model. The CUL4B-DDB1-ROC1 complex ubiquitinates STING at K370, promoting its degradation and inhibiting activation. Notably, CUL4B deficiency exacerbates LPS-induced EH, audio-vestibular dysfunction, and interferon-stimulated genes (ISG) upregulation, while double conditional knockout reverses these effects. Our study demonstrates that STING activation in vestibular macrophages contributes to audio-vestibular dysfunction and modulating this pathway has promising beneficial effects on audio-vestibular function in EH mice model, which is a potential therapeutic strategy for MD.