Activation of sympathetic nervous system drives dry eye onset via norepinephrine-β2-adrenergic receptor signaling in mice

Dry eye disease (DED) and sympathetic nervous system (SNS) activation have clear association with chronic environmental and psychogenic stress. However, the relationship and mechanism of SNS activation in dry eye pathogenesis remains elusive. Here we first found that the DED mice induced by chronic desiccating stress and scopolamine exhibited the SNS activation and elevated corneal norepinephrine (NE) contents. However, systemic SNS ablation with 6-OHDA and local NE depletion with DSP-4 treatment markedly alleviated the dry eye severity. More directly, topical application of NE phenocopied the dry eye syndrome in healthy mice, but not in mice with Adrb2 gene knockout, the dominant adrenergic receptor in cornea. In contrast, topical administration of selective Adrb2 antagonist ICI 118551 significantly attenuated the dry eye severity, including the increased tear secretion, improved corneal epithelial barrier function, and the reduced expressions of matrix-metalloproteinases, chemokines and inflammatory cytokines. Transcriptomic analysis and experimental validations underscored the strong links of top 10 downregulated pathways and dry eye-related inflammatory and immune responses, including TNF, NF-κB, chemokines and IL-17 signaling. Taken together, these results provide direct evidence of SNS activation in driving dry eye onset through NA-Adrb2 signaling pathway, which offers potential preventative and therapeutic approach for dry eye diseases.