CXCR5/NRF2 double knockout mice develop retinal degeneration phenotype at early adult age

Area of Science:

• Ophthalmology
• Genetics
• Cell Biology

Background:

• Retinal degeneration (RD) is a group of inherited disorders that affect the retina.
• The chemokine receptor CXCR5 and the transcription factor NRF2 play roles in ocular health.
• Understanding the interplay between CXCR5 and NRF2 in retinal health is crucial for developing new therapies.

Purpose of the Study:

• To characterize the retinal degeneration (RD) phenotype of CXCR5/NRF2 double knockout (DKO) mice at an early adult age.
• To investigate the molecular mechanisms underlying RD in DKO mice.
• To establish DKO mice as a potential animal model for RD research.

Main Methods:

• Generation of CXCR5/NRF2 DKO mice by breeding single knockout mice.
• Phenotypic assessment using fundus imaging, optical coherence tomography (OCT), Periodic acid-Schiff (PAS) staining, and immunofluorescence.
• Analysis of protein expression via Western blots and fluorescent microscopy.
• Assessment of photoreceptor cell apoptosis using cleaved caspase-3 and PNA-lectin staining.

Main Results:

• DKO mice exhibited hypopigmented spots, sub-RPE abnormalities, and aberrant RPE/sub-RPE depositions compared to controls.
• Increased sub-RPE deposition of IgG and AMD-associated proteins (e.g., β-amyloid, Apolipoprotein-E) observed in DKO mice.
• DKO mice showed upregulated AMD-associated proteins, microglia marker (TMEM119), and signs of epithelial-mesenchymal transition (increased CXCL13 and N-cadherin).
• Photoreceptor cell apoptosis was significantly increased in adult DKO mice.

Conclusions:

• CXCR5/NRF2-DKO mice develop key retinal degeneration characteristics at an early adult age.
• The DKO mouse model exhibits AMD-associated protein deposition and photoreceptor cell death.
• These findings suggest that CXCR5/NRF2-DKO mice are a promising preclinical model for studying retinal degeneration.