Platelet Endothelial Cell Adhesion Molecule-Dependent Leukocyte Transmigration Is an Essential Early Event in Endotoxin-Induced Uveitis

Endotoxin-induced uveitis (EIU) is an experimental model of infectious uveitis, a condition that accounts for 14% of uveitis cases, with an incidence of 19 per 100,000 population per year in the United States. Infectious uveitis typically requires 4 to 6 weeks of treatment and may become chronic or recurrent. Current therapies include corticosteroids and empiric anti-infective agents but are limited by complications related to immunosuppression. In a mouse model of EIU, C-C motif chemokine ligand (Ccl)-2 deficiency markedly reduced EIU severity, indicating an important role for Ccl2-driven inflammation. Neutrophils, or polymorphonuclear leukocytes (PMNs), are the dominant immune cells recruited in early-stage infectious uveitis, yet their interactions with C-C chemokine receptor (Ccr)-2⁺ monocytes (monocytes that respond to Ccl2), remain poorly understood. The role of PMNs in recruiting Ccr2⁺ monocytes has not been studied in the mouse model. In the mouse EIU model, PMN depletion resulted in an increase in Ccr2⁺ monocyte infiltration in the retina at peak disease, which persisted for 72 hours. PMN depletion improved the histology score in EIU mice but did not affect the clinical phenotype. In a more therapeutic approach, anti-platelet endothelial cell adhesion molecule (Pecam) antibody was used to block transmigration, demonstrating for the first time that transmigration in the retina is Pecam dependent. Anti-Pecam treatment resulted in the reduction of PMN accumulation in the retina as well as histologic and clinical manifestations of EIU.