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Cell-Type-Specific Complement Profiling in the ABCA4-/- Mouse Model of Stargardt Disease
Yassin Jabri1, Josef Biber2, Nundehui Diaz-Lezama2
1Department of Experimental Ophthalmology, Eye Clinic, University Hospital Regensburg, D-93053 Regensburg, Germany.
Insights
Stargardt macular degeneration involves ABCA4 gene mutations. This study reveals complement system overactivation in ABCA4-deficient mice retinas, suggesting a link to retinal degeneration.
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Stargardt macular degeneration is an inherited retinal disease.
- Mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene cause this condition.
- The role of the complement system in ABCA4-related retinal degeneration is not fully understood.
Purpose of the Study:
- To characterize the complement expression profile in ABCA4 knockout mouse retinas.
- To correlate complement findings with morphological markers of retinal degeneration.
- To investigate the impact of ABCA4 deficiency on complement homeostasis in the retina.
Main Methods:
- Analysis of complement gene and protein expression in ABCA4-/- mice.
- Morphological assessment of retinal degeneration.
- Measurement of complement C3b/C3 and C3d/C3 ratios in retinal tissues and serum.
- Evaluation of complement factor I (CFI) levels.
Main Results:
- ABCA4-/- mice exhibited enhanced retinal pigment epithelium (RPE) autofluorescence and inner retinal cell loss.
- Increased C3 expression and decreased CFI transcripts were observed in specific retinal cells of ABCA4-/- mice.
- Protein analysis confirmed reduced CFI and elevated C3b/C3 ratios in the retina and RPE/choroid of ABCA4-/- mice.
- Increased C3d/C3 ratio in serum of ABCA4-/- mice, with no change in CFI.
Conclusions:
- The findings suggest an overactive complement cascade in ABCA4-/- retinas.
- Complement dysregulation may contribute to pathological alterations like microglial activation and neurodegeneration.
- Maintaining complement homeostasis is crucial for retinal integrity.
Abstract:
Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4-/- retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4-/- mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4-/- mice expressed more c3 in the RPE and fewer cfi transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4-/-, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4-/- mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4-/- retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity.
