Abstract
Background: Ménière disease (MD) is a chronic inner ear disorder of unknown etiology. Although an immune-inflammatory link is suspected, the upstream triggers and cellular mechanisms connecting psychosocial stress to inner ear pathology remain poorly defined. This study aimed to investigate the role of stress-related, myeloid cell-derived inflammation in the progression of MD. Methods: This multi-cohort study involved 384 MD patients (62.5% female); and 138 healthy controls (HCs) (46.4% female). Perceived stress was evaluated in 110 MD patients and 65 HCs. Transcriptional profiles were characterized using RNA sequencing on peripheral whole blood (4 MD, 6 HC) and on sorted CD11b + myeloid cells versus CD11b-non-myeloid cells (8 MD, 6 HC). In a larger cross-sectional cohort (239 MD patients, 35 HCs), the association between serum inflammatory cytokines and audio-vestibular function was examined, with a subset (n = 42) followed up. Finally, in vitro experiments explored the regulatory effects of catecholamines and glucocorticoids on myeloid cells isolated from 23 MD patients and 26 HCs. Results: MD patients reported significantly higher levels of perceived stress compared to controls. RNA sequencing of peripheral blood revealed a distinct pro-inflammatory transcriptional signature in MD patients. Further analysis identified CD11b + myeloid cells as the primary source of this inflammation, showing significant upregulation of pro-inflammatory genes. Clinically, elevated serum levels of the myeloid-derived cytokine G-CSF were associated with poorer baseline audio-vestibular function, and a follow-up increase in G-CSF levels correlated with functional deterioration. Mechanistically, MD patients exhibited elevated plasma norepinephrine and increased β1-adrenergic receptor mRNA in myeloid cells. In vitro, blockade of the β-adrenergic-cAMP pathway attenuated pro-inflammatory cytokine production in these cells. Although systemic cortisol levels remained unchanged, the glucocorticoid receptor sensitivity of myeloid cells in MD patients was altered. Conclusion: Our study elucidates a potential pathophysiological axis in MD, where perceived psychosocial stress is linked to sympathetic nervous system overactivity. This, in turn, primes circulating myeloid cells for a pro-inflammatory response via the β-adrenergic pathway. The resultant systemic inflammation is closely associated with the severity and progression of audio-vestibular dysfunction. These findings suggest that targeting the stress-neuroendocrine-immune interface may offer novel therapeutic strategies for MD.