Glucocorticoid receptor inhibits Müller glial galectin-1 expression via DUSP1-dependent and -independent deactivation of AP-1 signalling.

Abstract

Galectin‐1/LGALS1 is a hypoxia‐induced angiogenic factor associated with diabetic retinopathy (DR). Recently, we elucidated a hypoxia‐independent pathway to produce galectin‐1 in Müller glial cells stimulated by interleukin (IL)‐1β. Here we revealed glucocorticoid receptor (GR)‐mediated inhibitory mechanisms for Müller glial galectin‐1/LGALS1 expression. Activator protein (AP)‐1 site in the LGALS1 enhancer region, to which activating transcription factor2, c‐Fos and c‐Jun bind, was shown to be essential for IL‐1β‐induced galectin‐1/LGALS1 expression in Müller cells. Ligand (dexamethasone or triamcinolone acetonide)‐activated GR induced dual specificity phosphatase (DUSP)1 expression via the glucocorticoid response element and attenuated IL‐1β‐induced galectin‐1/LGALS1 expression by reducing phosphorylation of these AP‐1 subunits following AKT and extracellular signal‐regulated kinase (ERK)1/2 deactivation. Moreover, activated GR also caused DUSP1‐independent down‐regulation of IL‐1β‐induced LGALS1 expression via its binding to AP‐1. Administration of glucocorticoids to mice attenuated diabetes‐induced retinal galectin‐1/Lgals1 expression together with AKT/AP‐1 and ERK/AP‐1 pathways. Supporting these in vitro and in vivo findings, immunofluorescence analyses showed co‐localization of galectin‐1 with GR and phosphorylated AP‐1 in DUSP1‐positive glial cells in fibrovascular tissues from patients with DR. Our present data demonstrated the inhibitory effects of glucocorticoids on glial galectin‐1 expression via DUSP1‐dependent and ‐independent deactivation of AP‐1 signalling (transactivation and transrepression), highlighting therapeutic implications for DR.