Alternative complement pathway deficiency ameliorates chronic smoke-induced functional and morphological ocular...

Area of Science:

• Ophthalmology
• Immunology
• Toxicology

Background:

• Age-related macular degeneration (AMD) is a leading cause of blindness, linked to genetics and environmental factors like smoking.
• The complement system is implicated in AMD, and smoking is a major risk factor.
• Previous studies show cigarette smoke exposure (CE) causes retinal defects, but the role of complement activation in this pathology is unclear.

Purpose of the Study:

• To investigate if complement activation is causative in cigarette smoke-induced ocular pathology.
• To determine which complement pathway is required for CE-mediated retinal damage.

Main Methods:

• Mice were exposed to cigarette smoke (CE) or filtered air for 6 months.
• Wildtype (WT) mice and mice lacking the complement alternative pathway (AP; CFB(-/-)) were analyzed using molecular, histological, electrophysiological, and behavioral methods.

Main Results:

• CE caused significant vision loss (rods and cones) and retinal thinning in WT mice.
• Complement C3d deposition indicated AP activation targeting the RPE/Bruch's membrane (BrM) complex.
• AP-deficient mice (CFB(-/-)) were protected from CE-induced ocular alterations.

Conclusions:

• Ocular pathology from CE is dependent on complement activation, specifically requiring the AP.
• These findings highlight the AP as a potential therapeutic target for smoke-induced eye diseases, including AMD.