A Stress-Neuroendocrine-Myeloid Inflammation Axis Is Associated with the Progression of Ménière's Disease

TL;DR

This study finds that stress may worsen Ménière's disease by triggering inflammation through myeloid cells, offering new insights into its progression and potential treatments.

Contribution

The study identifies a stress-neuroendocrine-myeloid inflammation axis as a novel mechanism underlying Ménière's disease progression.

Findings

MD patients showed higher perceived stress and a pro-inflammatory gene signature in myeloid cells.

Elevated G-CSF levels correlated with worse audio-vestibular function and disease progression.

Blocking the β-adrenergic-cAMP pathway reduced inflammation in myeloid cells from MD patients.

Abstract

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.

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.

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.

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.

Figures