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Published on: February 10, 2021
Complement component C3 plays a critical role in protecting the aging retina in a murine model of age-related macular
Jaimie Hoh Kam1, Eva Lenassi, Talat H Malik
1Institute of Ophthalmology, University College London, London, United Kingdom.
Insights
Strategies targeting complement component C3 (C3) for age-related macular degeneration (AMD) may be harmful. Both C3 deficiency and uncontrolled C3 activation negatively impact aged retinas, suggesting caution in therapeutic approaches.
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Complement component C3 (C3) is central to inflammation in age-related macular degeneration (AMD).
- Genetic variations in complement proteins, like complement factor H (CFH), influence C3 activation via the alternative pathway.
- Therapeutic strategies for AMD often consider C3 inhibition or CFH augmentation.
Purpose of the Study:
- To investigate the impact of C3 and CFH deficiencies on retinal integrity in aged mice.
- To evaluate the effects of genetic alterations in the complement system on retinal function and morphology.
Main Methods:
- Analysis of retinal function using electroretinography in aged mice.
- Morphological assessment of retinas via light and electron microscopy.
- Staining for amyloid β (Aβ) deposition, inflammation, and macrophage accumulation.
Main Results:
- Mice lacking both CFH and C3 (CFH(-/-).C3(-/-)) exhibited more severe retinal dysfunction than other groups.
- All mutant strains showed photoreceptor loss and thickened Bruch's membrane, with CFH(-/-).C3(-/-) mice showing greater severity.
- CFH(-/-).C3(-/-) mice had increased Aβ deposition, reduced macrophages, and heightened retinal inflammation.
Conclusions:
- Both uncontrolled C3 activation (CFH(-/-)) and complete C3 absence (CFH(-/-).C3(-/-), C3(-/-)) adversely affect aged retinas.
- These findings challenge the therapeutic efficacy of C3 inhibition in AMD.
- Further research is needed to understand the complex role of C3 in retinal health and disease.
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.
