Neutrophils as an important pathophysiologic cellular component in the onset of AMD

Abstract

AbstractVision loss from age‐related macular degeneration (AMD) is an expanding, major unmet problem due to the aging population worldwide. Inflammation has emerged as a potential cause of AMD, but how inflammation contributes to vision loss in AMD remains controversial despite intensive study around the world. Herein, we identify inflammatory signals that drive neutrophil infiltration into the retinas of early AMD patients and the Cryba1 conditional knockout mouse model that mimics an early AMD‐like phenotype. Specifically, we observed increased levels of IFNλ in early AMD that triggered neutrophil activation and lipocalin‐2 (LCN‐2) upregulation in these cells. NOD‐SCID immune‐deficient mice were injected intravenously with IFNλ activated bone marrow‐derived normal neutrophils labeled with red CMTPX dye. Ribbon‐scanning confocal microscopy (RSCM) of benzyl alcohol benzyl benzoate (BABB) cleared eyes, showed homing of neutrophils into the eye. In contrast, mice injected with IFNλ activated LCN‐2‐/‐ neutrophils showed fewer cells infiltrating the eye. LCN‐2 promotes inflammation and AMD‐like pathology by interacting with Disabled homolog2 (Dab2) and modulating integrin β1 levels to stimulate adhesion and transmigration of activated IL‐28R1 (IFNλ receptor) positive neutrophils into the retina. Inhibiting AKT2‐dependent signaling in the mouse model neutralizes IFNλ inflammatory signals, reducing LCN‐2‐mediated neutrophil infiltration into the retina and reversing early AMD‐like phenotype changes, thereby providing a potential therapeutic target for early AMD.