アクロレインは、ミュラー細胞からのCCL2産生を誘導することにより、マクロファージ走化性を介して網膜炎症を促進する

This study aimed to investigate the inflammatory mechanisms induced by the toxic aldehyde acrolein in proliferative diabetic retinopathy (PDR). N^ε-(3-formyl-3, 4-dehydropiperidino) lysine adduct (FDP-lys), an acrolein-binding protein, and chemokine (C-C motif) ligand-2 (CCL2) levels in human vitreous fluid obtained from patients with PDR were measured using Luminex assay and ELISA. A rat Müller glial cell line (TR-MUL5) was exposed to acrolein (10-50 μM), and CCL2 expression was evaluated using real-time PCR and ELISA. Macrophage (RAW264.7) migration under the presence of acrolein-stimulated TR-MUL5 was assessed using a Transwell assay. High mobility group box-1 (HMGB1) translocation in TR-MUL5 was examined by immunofluorescence and cell fractionation. These analyses demonstrated that FDP-lys and CCL2 concentrations in the vitreous of patients with PDR were markedly higher than those in controls (n = 12, p < 0.01), and a significant correlation was observed between the two (R = 0.60, p < 0.05). Acrolein stimulation upregulated Ccl2 expression in TR-MUL5 cells (3.5 ± 0.4-fold at 25 μM; 10 ± 1.4-fold at 50 μM, n = 3, p < 0.01) and increased CCL2 protein levels dose-dependently (n = 3, p < 0.01). Macrophage migration increased 2.2 ± 0.3-fold with acrolein-stimulated TR-MUL5 but was attenuated by the CCR2 inhibitor RS504393 (n = 3, p < 0.01). Acrolein-induced HMGB1 translocation was confirmed in TR-MUL5, and glycyrrhizin, an HMGB1 inhibitor, reduced CCL2 levels. In conclusion, acrolein promotes PDR progression by enhancing macrophage migration through CCL2 secretion and HMGB1 translocation in Müller cells.