C5a-Induced Autophagy Dysfunction Promotes Choroidal Neovascularization Through the ROS-Inflammatory Pathway

Area of Science:

• Ophthalmology
• Immunology
• Cell Biology

Background:

• Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults.
• Complement component 5a (C5a) is implicated in AMD pathogenesis, contributing to drusen formation and disease progression.

Purpose of the Study:

• To investigate how C5a exacerbates AMD by examining its interaction with autophagy, mitochondrial reactive oxygen species (ROS), and proinflammatory cytokines.
• To elucidate the role of C5a in choroidal neovascularization (CNV), a key feature of AMD.

Main Methods:

• Human retinal pigment epithelial (ARPE-19) cells were treated with C5a, and autophagy markers were analyzed.
• Mitochondrial ROS levels and cytokine secretion (VEGF, MCP-1, IL-6, IL-8) were quantified.
• A mouse model of laser-induced CNV was used to assess the in vivo effects of C5a, autophagy modulators, and ROS inhibitors.

Main Results:

• C5a stimulation increased autophagy markers (LC3-II, Beclin-1, p62/SQTSM1), mitochondrial ROS, and pro-CNV cytokine secretion.
• Autophagy activation and ROS inhibition significantly reduced C5a-induced cytokine release and CNV area.
• ROS inhibitors effectively diminished key cytokines (IL-6, IL-8, MCP-1, VEGF) and CNV progression.

Conclusions:

• C5a induces autophagy dysfunction and elevates mitochondrial ROS production.
• Mitochondrial ROS drives the release of cytokines that promote CNV formation in AMD.
• Modulating autophagy and inhibiting ROS represent potential therapeutic strategies for AMD.