Acrolein Promotes Retinal Inflammation Through Macrophage Chemotaxis by Inducing CCL2 Production From Müller Cells

Area of Science:

• Ophthalmology
• Toxicology
• Cell Biology

Background:

• Proliferative diabetic retinopathy (PDR) involves complex inflammatory mechanisms.
• Acrolein, a toxic aldehyde, is implicated in various pathologies.
• Understanding acrolein's role in PDR is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the inflammatory pathways mediated by acrolein in PDR.
• To assess the correlation between acrolein-binding protein adducts and CCL2 in PDR patients.
• To elucidate the cellular mechanisms by which acrolein influences Müller cells and macrophage migration.

Main Methods:

• Quantification of N^ε-(3-formyl-3, 4-dehydropiperidino) lysine adduct (FDP-lys) and CCL2 in human vitreous fluid using Luminex and ELISA.
• In vitro exposure of rat Müller glial cells (TR-MUL5) to acrolein, followed by assessment of CCL2 expression via real-time PCR and ELISA.
• Evaluation of macrophage migration using Transwell assays and examination of High mobility group box-1 (HMGB1) translocation in TR-MUL5 cells.

Main Results:

• Elevated levels of FDP-lys and CCL2 were observed in the vitreous fluid of PDR patients compared to controls, with a significant positive correlation between them.
• Acrolein stimulation dose-dependently upregulated CCL2 expression in TR-MUL5 cells.
• Acrolein-stimulated Müller cells enhanced macrophage migration, an effect inhibited by a CCR2 antagonist, and acrolein induced HMGB1 translocation, which was reduced by an HMGB1 inhibitor.

Conclusions:

• Acrolein plays a significant role in the inflammatory processes of PDR.
• Acrolein promotes PDR progression by increasing CCL2 secretion and HMGB1 translocation in Müller cells, thereby enhancing macrophage migration.
• Targeting acrolein-mediated pathways, including CCL2 and HMGB1, may offer therapeutic strategies for PDR.