Retinal pigment epithelium-derived extracellular vesicles mediate outer blood retinal barrier disruption in response...

Age-related macular degeneration (AMD) is a leading cause of vision loss among the elderly, primarily affecting the central vision. This progressive degenerative disease is characterized by the dysregulation and degeneration of the retinal pigment epithelium (RPE), a crucial cell layer beneath the photoreceptors that maintains outer retinal homeostasis. Emerging evidence suggests that during AMD, stressed RPE cells release extracellular vesicles (EVs) carrying bioactive cargo, which may compromise the outer blood-retinal barrier (oBRB) and accelerate disease progression. This study explores the role of EVs released by RPE cells under pro-inflammatory conditions in disrupting retinal integrity.

Highly polarized primary cultures of porcine RPE (pRPE) and porcine eyecups with the RPE exposed were treated with tumor necrosis factor (TNF), lipopolysaccharide (LPS), or EVs derived from inflamed RPE cells. Additionally, Balb/c mice were intravitreally injected with RPE-derived EVs.

We show that EVs secreted by the apical membrane domain of porcine RPE cells exposed to LPS or TNF impair the RPE monolayer in polarized cultures, disrupt the oBRB in ex vivo porcine eyecups, and induce retinal structural damage detected in vivo in Balb/c mice. Intravitreal injection of LPS-derived EVs triggers photoreceptor and RPE layers thinning, increases reactivity in astrocytes and Müller cells, promotes pro-inflammatory microglial activation and recruitment, particularly into the outer retina, and elevates retinal apoptosis. Mechanistically, matrix metalloproteinases (MMPs) activity mediates EV-induced RPE monolayer disruption, whereas MMPs activity inhibition mitigates these effects.

Our findings reveal a novel EV-driven mechanism contributing to retinal degeneration progression, highlighting inflammation-derived apical EVs as key players in diseases involving oBRB dysfunction. Targeting EV-mediated signaling and MMPs activity may offer therapeutic strategies for preserving retinal structure and function in inflammatory retinal diseases such as age-related macular degeneration.