title: Complement component C3 plays a critical role in protecting the aging retina in a murine model of age-related macular degeneration.
abstract: Complement component C3 is the central complement component and a key inflammatory protein activated in age-related macular degeneration (AMD). AMD is associated with genetic variation in complement proteins that results in enhanced activation of C3 through the complement alternative pathway. These include complement factor H (CFH), a negative regulator of C3 activation. Both C3 inhibition and/or CFH augmentation are potential therapeutic strategies in AMD. Herein, we examined retinal integrity in aged (12 months) mice deficient in both factors H and C3 (CFH(-/-).C3(-/-)), CFH alone (CFH(-/-)), or C3 alone (C3(-/-)), and wild-type mice (C57BL/6). Retinal function was assessed by electroretinography, and retinal morphological features were analyzed at light and electron microscope levels. Retinas were also stained for amyloid β (Aβ) deposition, inflammation, and macrophage accumulation. Contrary to expectation, electroretinograms of CFH(-/-).C3(-/-) mice displayed more severely reduced responses than those of other mice. All mutant strains showed significant photoreceptor loss and thickening of Bruch's membrane compared with wild-type C57BL/6, but these changes were greater in CFH(-/-).C3(-/-) mice. CFH(-/-).C3(-/-) mice had significantly more Aβ on Bruch's membrane, fewer macrophages, and high levels of retinal inflammation than the other groups. Our data show that both uncontrolled C3 activation (CFH(-/-)) and complete absence of C3 (CFH(-/-).C3(-/-) and C3(-/-)) negatively affect aged retinas. These findings suggest that strategies that inhibit C3 in AMD may be deleterious.
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Jaimie
authors.initials: J
authors.lastname: Hoh Kam
authors.forename: Eva
authors.initials: E
authors.lastname: Lenassi
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.forename: Glen
authors.initials: G
authors.lastname: Jeffery
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016570:Bruch Membrane / Q000648:ultrastructure; D003176:Complement C3 / Q000172:deficiency / Q000502:physiology*; D017242:Complement Factor H / Q000172:deficiency; D004195:Disease Models, Animal; D004596:Electroretinography; D008268:Macular Degeneration / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000502:physiology; D012160:Retina / Q000378:metabolism / Q000502:physiology*; D055213:Retinal Pigment Epithelium / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003176:Complement C3; D017242:Complement Factor H