Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.

Area of Science:

• Cell Biology
• Ophthalmology
• Immunology

Background:

• Autophagy and lysosomal degradation are critical for cellular protection against oxidative stress.
• Lysosome-associated membrane protein 2 (Lamp2) is essential for autophagosome maturation and lysosome biogenesis.

Purpose of the Study:

• To investigate the role of Lamp2 in maintaining retinal health under oxidative stress.
• To determine the impact of Lamp2 deficiency on retinal pigment epithelium (RPE) integrity and the inflammatory response.

Main Methods:

• Induction of oxidative stress using sodium iodate (NaIO3) in Lamp2 knockout (KO) and wild-type mice.
• Assessment of retinal histopathology, RPE morphology, and microglial/macrophage involvement via immunostaining, flow cytometry, and gene expression analysis.
• Evaluation of the therapeutic effect of macrophage depletion using clodronate.

Main Results:

• Lamp2 KO mice exhibited significant RPE degeneration and outer nuclear layer thinning after NaIO3 administration, unlike wild-type mice.
• Increased infiltration and activation of microglia and macrophages were observed in the retinas of Lamp2 KO mice.
• Macrophage chemoattractant protein 1, macrophage inflammatory protein 1β, Il-1β, and Il-6 levels were elevated in Lamp2 KO retinas.
• Macrophage depletion prevented NaIO3-induced RPE damage and inflammatory cell infiltration in Lamp2 KO mice.

Conclusions:

• Lamp2 deficiency potentiates oxidative stress-induced RPE degeneration in vivo.
• Lysosomal dysfunction promotes macrophage infiltration and triggers neurotoxic inflammation in the retina.
• Targeting lysosomal function may offer therapeutic strategies for retinal diseases associated with oxidative stress and inflammation.