Ccl2/Cx3cr1-deficient mice: an animal model for age-related macular degeneration
Chi-Chao Chan1, Robert J Ross, Defen Shen
1Section of Immunopathology, Laboratory of Immunology, National Eye Institute, Bethesda, MD 20892-1857, USA. chanc@nei.nih.gov
Background/Aims:
Senescent Ccl2-/- mice develop cardinal features of human age-related macular degeneration (AMD). Loss-of-function single-nucleotide polymorphisms within CX3CR1 are associated with AMD.
Methods:
We generated Ccl2-/-/Cx3cr1-/- [double-knockout (DKO)] mice and evaluated the eyes using fundoscopy routine histology, immunochemistry, biochemistry and proteomics.
Results:
At 6 weeks old, all DKO mice developed AMD-like retinal lesions such as abnormal retinal pigment epithelium cells, drusen, photoreceptor atrophy and choroidal neovascularization, which progressed with age and reversed with high omega-3 long-chain polyunsaturated fatty acid diet. N-retinylidene-N-retinylethanolamine (A2E), a major lipofuscin fluorophore, illustrated by an emission peak at approximately 600 nm, was significantly higher in DKO retinal pigment epithelium. Decreased ERp29 was found in the retina of DKO mice.
Conclusion:
A broad spectrum of AMD pathologies with early onset and high penetrance in these mice implicate certain chemokines, A2E and endoplasmic reticulum proteins in AMD pathogenesis.
Insights
Senescent mice lacking Ccl2 and Cx3cr1 develop age-related macular degeneration (AMD) features. High omega-3 fatty acids reversed these AMD pathologies, implicating chemokines and A2E in disease.
Area of Science:
- Ophthalmology
- Genetics
- Immunology
Background:
- Senescent Ccl2-/- mice exhibit cardinal features of human age-related macular degeneration (AMD).
- Loss-of-function single-nucleotide polymorphisms in CX3CR1 are linked to AMD.
- Chemokines play a role in the pathogenesis of AMD.
Purpose of the Study:
- To investigate the role of combined Ccl2 and Cx3cr1 deficiency in AMD development.
- To evaluate the impact of omega-3 fatty acids on AMD-like pathologies in a mouse model.
Main Methods:
- Generation of Ccl2-/-/Cx3cr1-/- (double-knockout, DKO) mice.
- Ocular evaluation using fundoscopy, histology, immunochemistry, biochemistry, and proteomics.
- Dietary intervention with high omega-3 long-chain polyunsaturated fatty acids.
Main Results:
- DKO mice developed early-onset, high-penetrance AMD-like retinal lesions, including abnormal retinal pigment epithelium, drusen, photoreceptor atrophy, and choroidal neovascularization.
- Accumulation of N-retinylidene-N-retinylethanolamine (A2E) was significantly higher in DKO retinal pigment epithelium.
- Dietary supplementation with omega-3 fatty acids reversed AMD pathologies in DKO mice.
- Decreased ERp29 levels were observed in the retinas of DKO mice.
Conclusions:
- The Ccl2-/-/Cx3cr1-/- mouse model recapitulates key features of human AMD.
- Chemokines, A2E, and endoplasmic reticulum proteins are implicated in AMD pathogenesis.
- Omega-3 fatty acids demonstrate therapeutic potential for AMD.
