A gatekeeper mechanism of the noradrenergic neural control of tear secretion via the NA-Adra1a-Ucp2 pathway

Tears are mainly secreted from the lacrimal gland under precise controls by autonomic neural response to external sensory and psychogenic emotional stimulation. Dynamic volume and compositional changes of tears may lead to development of dry eye disease. The role of sympathetic nerve system (SNS) in controlling tear secretion and the noradrenergic neural circuit projecting from brain to lacrimal gland remain unexplored. Here, we discovered the dense sympathetic innervation of mouse lacrimal gland and investigated its physiological role in regulating tear production. In response to dry eye stimuli, SNS became overactivated with high noradrenaline (NA) in the lacrimal gland. Using gain- and loss-of-functional approaches, including pharmacologic, surgical, chemogenetic manipulations, and genetic knockout mice of specific adrenergic receptors, we demonstrated that both SNS ablation and NA blockage markedly increased tear volume and alleviated dry eye diseases. Mechanistically, activation of SNS released NA to reduce tear secretion through binding to α1a-adrenergic receptor (Adra1a) that targeted mitochondrial Ucp2 in the acinar and myoepithelial cells of the lacrimal gland. Consequently, antagonization of NA and Ucp2 markedly increased tear secretion. Using a retrograde neuronal tracing technique in combination with physiologic experiments of tear reduction and hypersecretion, we identified a novel noradrenergic neural circuit projecting from the brain locus coeruleus to the lacrimal gland and the orchestrated controlling of parasympathetic and sympathetic nervous system for tear secretion. Together, our data define a novel NA-Adra1a-Ucp2 signaling pathway as a gatekeeper mechanism for controlling tear secretion from the lacrimal gland. These findings provide novel mechanistic insights into sympathetic role in tear secretion and potential therapeutic options for treatment of dry eye disease.