Involvement of trabecular meshwork phagocytic suppression by sympathetic norepinephrine in nocturnal intraocular pressure rise

Intraocular pressure (IOP) is important in glaucoma development and depends on aqueous humor (AH) dynamics, involving inflow from the ciliary body and outflow through the trabecular meshwork (TM). IOP has a circadian rhythm entrained by sympathetic noradrenaline (NE) or adrenal glucocorticoids (GCs). Here, we investigated the involvement of GC and NE in AH outflow. Pharmacological prevention of inflow/outflow in mice indicated an AH outflow increase during day. Although TM phagocytosis can determine AH drainage, only NE showed a non-self-sustained inhibitory effect in phagocytosis of immortalized human TM cells. Pharmacological approach and RNA interference identified β1-adrenergic receptor (AR)-mediated cAMP-EPAC-SHIP1 signal activation by ablation of phosphatidylinositol triphosphate regulating phagocytic cup formation. Furthermore, pharmacological instillation in mice revealed the role of β1-AR-EPAC-SHIP1 pathway in nocturnal IOP rise. These suggest that IOP rhythm is partially regulated by this pathway. This first demonstration of TM phagocytosis suppression by NE could be useful in glaucoma management.