A gatekeeper sympathetic control of lacrimal tear secretion and dry eye onset through the NA-Adra1a-Ucp2 pathway

Tear secretion from the lacrimal gland is essential for maintaining ocular surface homeostasis, and its insufficiency causes aqueous-deficient dry eye. Unlike the well-established parasympathetic neuronal regulation, the role of sympathetic nervous system (SNS) in tear secretion remains controversial. Here, we demonstrate the intact sympathetic innervation in lacrimal gland and its activation under multiple dry eye stresses. Pharmacological, surgical, and genetic blockade of SNS increases tear secretion and alleviates dry eye signs. Mechanistically, SNS-driven noradrenaline (NA) release activates α1a-adrenergic receptor (Adra1a) in acinar and myoepithelial cells to regulate mitochondrial Ucp2 and tear secretion. Systemic and local delivery of Adra1a antagonists, including silodosin and tamsulosin, improves tear secretion and reduces corneal lesions in multiple dry eye mouse models. In addition, we identify the brain locus coeruleus as an upstream driver orchestrating sympathetic regulation of lacrimal secretion. Overall, these findings reveal a gatekeeper role of SNS in tear secretion and offer potential therapeutic strategies for dry eye disease.