Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal...

Area of Science:

• Ophthalmology
• Immunology
• Cell Biology

Background:

• Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD) with significant unmet medical needs.
• Genetic factors, particularly complement gene polymorphisms, are linked to AMD, but the precise role of complement activation in retinal atrophy is unclear.

Purpose of the Study:

• To investigate the role of complement activation on photoreceptor outer segments (POS) in the pathogenesis of geographic atrophy (GA).
• To determine the contribution of classical and alternative complement pathways and peripheral blood monocytes in photoreceptor degeneration.

Main Methods:

• Demonstrated complement activation on POS in retinas peripheral to GA lesions.
• Utilized mouse models of retinal degeneration to assess the impact of complement activation on photoreceptor function.
• Investigated the role of C5a-mediated monocyte recruitment and the effect of inhibiting complement convertases.

Main Results:

• Photoreceptor outer segments (POS) activate classical and alternative complement pathways when exposed to serum after blood-retinal barrier breakdown.
• Complement activation on photoreceptors contributed to photoreceptor dysfunction in mouse models, dependent on C5a-mediated monocyte recruitment.
• Inhibition of complement C3 and C5 convertases was necessary to prevent progressive degeneration of photoreceptor rods and cones.

Conclusions:

• Complement activation on POS is implicated in localized retinal degeneration associated with GA.
• Systemic complement proteins and peripheral blood monocytes are critical effectors in this process.
• Targeting complement pathways offers a potential therapeutic strategy for GA.