Retinal Müller Cell-Released Exosomal MiR-92a-3p Delivers Interleukin-17A Signal by Targeting Notch-1 to Promote...

Area of Science:

• Ophthalmology
• Cell Biology
• Molecular Biology

Background:

• Diabetic retinopathy (DR) involves inflammatory processes.
• Interleukin-17A (IL-17A), a pro-inflammatory cytokine, is linked to DR development.
• The precise mechanisms of IL-17A's impact on DR require further elucidation.

Purpose of the Study:

• To investigate the role of exosomal microRNAs (miRNAs) in mediating IL-17A signaling from Müller cells (MCs) to retinal ganglion cells (RGCs) in DR.
• To identify specific miRNAs involved in this intercellular communication pathway.
• To explore potential therapeutic targets for DR based on these findings.

Main Methods:

• Isolation and characterization of exosomes from cultured MCs.
• High-throughput sequencing to identify differentially expressed miRNAs in exosomes.
• Dual-luciferase reporter assay to confirm the targeting relationship between miR-92a-3p and Notch-1.
• In vitro experiments using cultured MCs and RGCs treated with high glucose (HG), IL-17A, and specific miRNA modulators.
• In vivo studies involving streptozotocin (STZ)-induced DR mice subjected to intravitreal exosome injections.

Main Results:

• IL-17A treatment upregulated miR-92a-3p in MC-derived exosomes, an effect blocked by anti-IL-17A antibody.
• Exosomes from IL-17A-treated MCs downregulated Notch-1 in RGCs, leading to increased neuronal death.
• miR-92a-3p inhibition suppressed these IL-17A effects, while mimic enhanced them.
• In STZ-induced DR mice, intravitreal exosomes from IL-17A-treated MCs reduced retinal Notch-1 and increased RGC apoptosis, an effect counteracted by miR-92a-3p inhibitor.

Conclusions:

• MC-released exosomal miR-92a-3p transmits IL-17A signals by inhibiting Notch-1, thereby accelerating DR progression.
• Intravitreal administration of exosomes carrying a miR-92a-3p inhibitor presents a potential therapeutic strategy for DR.