Immune Checkpoint PD‐L1 Modulates Retinal Microglial Activation to Alleviate Vascular Leakage in Choroidal Neovascularization via ERK

Abstract Neovascular age‐related macular degeneration (NVAMD) is a common retinal disease causing vision loss in the elderly. Neuroinflammation significantly contributes to NVAMD's etiology. This study explores the role of Programmed cell death ligand 1 (PD‐L1), an immune checkpoint (ICP) in microglia, known for limiting neuroinflammation in neurodegenerative diseases, and its potential function in NVAMD. This work finds increased PD‐L1 expression in retinal microglia following laser injury. PD‐L1 knockout (KO) or inhibitory PD‐L1 antibody treatment worsens vascular leakage and neoangiogenesis in a laser‐induced NVAMD mouse model, effects reversible by microglia depletion with PLX5622. This study underscores that choroidal neovascularization (CNV) may be regulated by multiple mechanisms, with PD‐L1 modulation representing one of these pathways. Blocking PD‐L1 elevated proinflammatory factors and p‐ERK levels, indicating microglial overactivation in NVAMD. Conversely, enhancing PD‐L1 signaling reduced neuroinflammation and neovascularization via ERK. These findings highlight PD‐L1's role in neoangiogenesis and neuroinflammation in NVAMD, suggesting its potential as a target for immunomodulatory treatment in NVAMD.