Investigative ophthalmology & visual science · 2025
Activation of Sympathetic Nervous System Drives Dry Eye Onset Via Norepinephrine-β2-Adrenergic Receptor Signaling in Mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Qu Mingli, Bai Xiaofei, Zhang Mengyao, Wu Jingyi, Wan Lei, Li Xiaoyu, Wang Qun, Cong Lin, Qi Benxiang, Zhou Qingjun
Аннотация
PURPOSE: Dry eye disease (DED) and sympathetic nervous system (SNS) activation have clear association with chronic environmental and psychogenic stress. However, the relationship of SNS activation with DED remains incompletely understood. This study aims to explore the role and mechanism of SNS activation in dry eye pathogenesis.
METHODS: DED was induced in mice using scopolamine under desiccating stress. Systemic SNS ablation and local norepinephrine (NE) depletion were performed through intraperitoneal 6-OHDA and subconjunctival DPS-4 injection. Topical NE was applied to healthy and Adrb2-/- mice. A selective β2-adrenergic receptor (β2-AR) antagonist, ICI 118,551, was administered topically to evaluate its therapeutic potential. Tear secretion, corneal epithelial barrier function, expressions of matrix-metalloproteinases, chemokines, and inflammatory cytokines were assessed. Transcriptomic analysis identified key pathways, followed by experimental validation with human corneal epithelial cells (HCECs).
RESULTS: DED mice showed apparent SNS activation with elevated corneal NE contents. Systemic SNS ablation and local NE depletion alleviated dry eye severity. Topical NE administration induced dry eye signs in healthy mice, but not in Adrb2-/- mice. ICI 118,551 improved tear secretion, corneal epithelial barrier function, and reduced inflammation. Transcriptomic analysis revealed that the top 10 downregulated pathways were strongly associated with dry eye-related inflammatory responses, including TNF, NF-κB, chemokines, and IL-17 signaling pathways. In vitro, ICI 118,551 inhibited NF-κB activation and inflammatory cytokines expression in HCECs under hyperosmotic stress.
CONCLUSIONS: This study provides direct evidence that SNS activation drives dry eye onset through the NE-β2-AR signaling pathway, offering a potential therapeutic target for dry eye diseases.
METHODS: DED was induced in mice using scopolamine under desiccating stress. Systemic SNS ablation and local norepinephrine (NE) depletion were performed through intraperitoneal 6-OHDA and subconjunctival DPS-4 injection. Topical NE was applied to healthy and Adrb2-/- mice. A selective β2-adrenergic receptor (β2-AR) antagonist, ICI 118,551, was administered topically to evaluate its therapeutic potential. Tear secretion, corneal epithelial barrier function, expressions of matrix-metalloproteinases, chemokines, and inflammatory cytokines were assessed. Transcriptomic analysis identified key pathways, followed by experimental validation with human corneal epithelial cells (HCECs).
RESULTS: DED mice showed apparent SNS activation with elevated corneal NE contents. Systemic SNS ablation and local NE depletion alleviated dry eye severity. Topical NE administration induced dry eye signs in healthy mice, but not in Adrb2-/- mice. ICI 118,551 improved tear secretion, corneal epithelial barrier function, and reduced inflammation. Transcriptomic analysis revealed that the top 10 downregulated pathways were strongly associated with dry eye-related inflammatory responses, including TNF, NF-κB, chemokines, and IL-17 signaling pathways. In vitro, ICI 118,551 inhibited NF-κB activation and inflammatory cytokines expression in HCECs under hyperosmotic stress.
CONCLUSIONS: This study provides direct evidence that SNS activation drives dry eye onset through the NE-β2-AR signaling pathway, offering a potential therapeutic target for dry eye diseases.