Fractalkine isoforms differentially regulate microglia-mediated inflammation and enhance visual function in the...

Area of Science:

• Ophthalmology
• Neuroscience
• Immunology

Background:

• Diabetic retinopathy (DR) affects 200 million people globally, causing retinal tissue damage via microglial activation and inflammation.
• The fractalkine (FKN) and CX3CR1 pathway is crucial for regulating microglial function; deficiencies exacerbate DR pathology.
• Understanding microglia regulation is key to developing effective DR treatments.

Purpose of the Study:

• To investigate the therapeutic potential of soluble fractalkine (sFKN) gene therapy in preventing diabetic retinopathy.
• To elucidate the mechanisms by which sFKN influences microglial activation, inflammation, and retinal health in a diabetes model.

Main Methods:

• Recombinant adeno-associated viral vectors (rAAV) expressing membrane-bound FKN (mFKN) or sFKN were administered to retinas.
• High-resolution confocal imaging and mRNA sequencing were employed to analyze retinal tissues.
• Evaluated microglia morphology, gene expression, neuronal and vascular health, and inflammatory markers in diabetic mouse models.

Main Results:

• Prophylactic intra-vitreal administration of rAAV-sFKN, but not rAAV-mFKN, protected vasculature and neurons in FKN knockout retinas.
• rAAV-sFKN treatment reduced microgliosis, mitigated inflammation, and improved optic nerve health.
• sFKN therapy prevented fibrin(ogen) leakage and improved visual acuity in diabetic mice.

Conclusions:

• Soluble fractalkine (sFKN) gene therapy offers a novel neuroprotective and vasculoprotective approach for diabetic retinopathy.
• sFKN regulates microglia-mediated inflammation, presenting a promising translational strategy to prevent diabetes-associated blindness.