Psychological stress induces dysfunction in the lacrimal gland through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis.

Chronic psychosocial stress is increasingly recognized as a key risk factor for dry eye disease, potentially because of its disruption of the circadian transcriptome and lacrimal gland function, which impacts eye health. In this study, we test this hypothesis by using two mouse models (high platform and restraint experiments) of psychological stress and report that both models uniquely alter the circadian transcriptome and signaling pathways of the lacrimal gland. Psychosocial stress significantly affects the normal rhythmic oscillations of extraorbital lacrimal gland (ELG) immune cell trafficking, secretion response, and lipid deposition. Both models significantly reduce the volume of stimulated lacrimal secretions as well as the recruitment of immune cells to the lacrimal gland. Importantly, treatment with beta-adrenergic receptor blockers or glucocorticoid synthesis inhibitors significantly improves these secretory functions and histopathological changes. Collectively, these findings demonstrate the detrimental effects of chronic psychosocial stress on lacrimal gland circadian transcriptome homeostasis and suggest potential clinical applications for patients with both psychological stress and dry eye disease.