Project description:Meniere’s disease (MD) is a common chronic inner ear disease of largely unknown etiology. Several psychobehavioral stressors and alterations in the immune system have been linked to MD attacks and disease progression. Nevertheless, the molecular basis of alterations in systemic immunity in individuals with MD remains unclear. This study aimed to demonstrate the roles of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis in patients with MD in regulating the lineage commitment and response pattern of myeloid cells and the potential implications on the function of the inner ear in MD. The peripheral blood transcriptome from patients with MD showed elevated levels of inflammation and decreased antiviral response, and myeloid cells were the main source of conserved transcriptional response to adversity (CTRA)-related inflammation. The expression of transcription factors regulating myeloid lineage commitment was altered, and flow cytometry analysis showed an expanded monocyte population, characterized by an increased subset of immature proinflammatory monocytes. Sympathetic signaling was activated in patients with MD, as evident by elevated norepinephrine levels and up-regulated adrenergic receptor β1 expression. LPS-induced inflammation in vitro was almost completely reversed by β blockers and an adenylate cyclase inhibitor in MD myeloid cells, and partially reversed by β1 and β2 subtypes, suggesting that the β-ADR-cAMP signaling pathway mediates exaggerated proinflammatory responses in myeloid cells. Although no significant change was observed in plasma cortisol levels in patients with MD, the increased ratio of the glucocorticoid receptor NR3C1 to the mineralocorticoid receptor NR3C2 suggested that MD myeloid cells were more sensitive to glucocorticoids. In vitro experiments confirmed that glucocorticoids significantly reduce LPS-induced inflammation. G-CSF levels were significantly elevated in patients with MD and correlated well with the levels of other cytokines. Cross-sectional and longitudinal follow-up data showed that the group with high or increased G-CSF over time had worse inner ear function, reflecting the potential effect of systemic inflammation on inner ear function in patients with MD. Our data provide an additional mechanism to elucidate the regulation of the transcriptome of MD myeloid cells by the HPA axis and SNS, and their potential effects on inner ear function. Conclusively, our results imply that good management of stress and prevention of CTRA development may benefit patients with MD.

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Conserved transcriptional response to adversity-related inflammation contributes to Meniere’s disease progression

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