The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye

Area of Science:

• Ophthalmology
• Immunology
• Neuroscience

Background:

• Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, linked to aberrant immune responses.
• Reactive phagocytes and gliosis are implicated in AMD pathogenesis.
• The translocator protein (18 kDa) (TSPO) is a biomarker for reactive gliosis, but its role in retinal diseases is unclear.

Purpose of the Study:

• To investigate the role of TSPO in the pathogenesis of neovascular AMD.
• To determine if targeting TSPO can prevent AMD progression.
• To elucidate the mechanism by which TSPO influences retinal immune responses.

Main Methods:

• Conditional deletion of TSPO in microglia using Cx3cr1^CreERT2:TSPO^fl/fl mice.
• Pharmacological inhibition of TSPO using the synthetic ligand XBD173.
• Laser-induced mouse model of neovascular AMD.
• Assessment of phagocyte reactivity, neoangiogenesis, vascular leakage, and reactive oxygen species (ROS) production.

Main Results:

• TSPO deletion or XBD173 treatment prevented phagocyte reactivity in the AMD model.
• Neoangiogenesis and vascular leakage were significantly reduced in TSPO-deficient or XBD173-treated mice.
• TSPO was identified as a key regulator of NOX1-dependent ROS production in the retina.

Conclusions:

• TSPO plays a critical role in regulating retinal phagocyte reactivity and neuroinflammation in AMD.
• Targeting TSPO offers a promising therapeutic strategy for AMD.
• TSPO inhibition may provide both immunomodulatory and antioxidant benefits for AMD treatment.