Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

Jabri, Yassin; Biber, Josef; Diaz-Lezama, Nundehui; Grosche, Antje; Pauly, Diana

doi:10.3390/ijms21228468

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Cell-Type-Specific Complement Profiling in the ABCA4^−/− Mouse Model of Stargardt Disease

^1,†,

^2,†,

²,

^2,*

and

Diana Pauly

^3,4,*

Department of Experimental Ophthalmology, Eye Clinic, University Hospital Regensburg, D-93053 Regensburg, Germany

Department of Physiological Genomics, Biomedical Center, Ludwig Maximilians University Munich, D-82152 Planegg-Martinsried, Germany

Experimental Ophthalmology, Philipps-University Marburg, D-35043 Marburg, Germany

⁴

Department of Ophthalmology, University Hospital Regensburg, D-93053 Regensburg, Germany

Authors to whom correspondence should be addressed.

^†

These authors have equally contributed.

Int. J. Mol. Sci. 2020, 21(22), 8468; https://doi.org/10.3390/ijms21228468

Received: 9 October 2020 / Revised: 2 November 2020 / Accepted: 9 November 2020 / Published: 11 November 2020

(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 2.0)

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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. View Full-Text

Keywords: Stargardt macular degeneration; ABCA4; cell-type-specific complement expression; C3; CFI

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Jabri, Y.; Biber, J.; Diaz-Lezama, N.; Grosche, A.; Pauly, D. Cell-Type-Specific Complement Profiling in the ABCA4^−/− Mouse Model of Stargardt Disease. Int. J. Mol. Sci. 2020, 21, 8468. https://doi.org/10.3390/ijms21228468

AMA Style

Jabri Y, Biber J, Diaz-Lezama N, Grosche A, Pauly D. Cell-Type-Specific Complement Profiling in the ABCA4^−/− Mouse Model of Stargardt Disease. International Journal of Molecular Sciences. 2020; 21(22):8468. https://doi.org/10.3390/ijms21228468

Chicago/Turabian Style

Jabri, Yassin, Josef Biber, Nundehui Diaz-Lezama, Antje Grosche, and Diana Pauly. 2020. "Cell-Type-Specific Complement Profiling in the ABCA4^−/− Mouse Model of Stargardt Disease" International Journal of Molecular Sciences 21, no. 22: 8468. https://doi.org/10.3390/ijms21228468

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Cell-Type-Specific Complement Profiling in the ABCA4^−/− Mouse Model of Stargardt Disease

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