IFN-β immunomodulation and complement receptor analysis in a mouse model of age-related macular degeneration (AMD)

Chronic activation of microglia is associated with retinal degeneration, which makes them a potential therapeutic target for retinal degenerative diseases including age-related macular degeneration (AMD). Furthermore, overactivation of the alternative complement pathway is generally accepted as the main driver for AMD disease progression and microglia are important producers of local complement and express complement receptors themselves. Interferon-beta (IFN-β) is a potent immune regulator, commonly used for the treatment of multiple sclerosis patients. Here, we aim to elucidate whether modulation of microglia via IFN-β may dampen mononuclear phagocyte reactivity and thereby protect from retinal degeneration in a light damage paradigm mimicking some features of dry AMD. We further investigate the involvement of anaphylatoxin signaling during retinal degeneration using anaphylatoxin receptor knockout mice. BALB/cJ mice received intraperitoneal injections of 10,000 U IFN-β or vehicle every other day; starting at the day of exposure to 15,000 lux white light for one hour. Systemic treatment with IFN-β partially enhanced IFN-α/β receptor (IFNAR) signaling in the retina and reduced the number of reactivated microglia in the subretinal space. However, four days after light damage neither decreased expression of complement factors nor rescue of retinal thickness was observed. Bright white light with an intensity of 10,000 lux for 30 minutes was applied for complement component 3a receptor 1 (C3ar1) or complement component 5a receptor 1 (C5ar1) mice. Full body knockout mice of either C3aR1 or C5aR1 were tested, but none led to mitigated microglia migration to the subretinal space or decreased expression of complement factors after light damage compared to wildtype. However, a partial rescue of retinal thickness was shown in C3aR1 knockout mice, which was mirrored by significant less membrane attack complex (MAC) occurrence in the outer retina. We conclude that IFNAR signaling modulate retinal microglia but cannot prevent strong retinal degeneration as elicited by acute white light damage. Contrarily, deletion of the anaphylatoxin receptor C3aR1 cannot modulate retinal microglia but decelerate retinal degeneration through interference in the complement pathway and thus decreased MAC assembling