Liver X Receptor–Growth Differentiation Factor 15 Activation Drives Profibrotic Changes in the Aqueous Outflow Tract of Uveitic Glaucoma

Abstract

Cytomegalovirus (CMV)–induced anterior uveitis is linked to increased intraocular pressure, suggesting profibrotic changes in the eye's drainage system. Previous studies on the aqueous humor (AH) of patients with CMV uveitic glaucoma (UG) highlighted the activation of the liver X receptor (LXR) pathway, yet a potential that it has a role in increased intraocular pressure remained unelucidated. Herein, the LXR pathway's role in AH outflow in UG was explored. Global transcriptional analysis revealed that LXR activation primarily induces transforming growth factor-β signaling, with growth differentiation factor 15 (GDF-15), a growth factor in the transforming growth factor-β superfamily, being one of the most up-regulated genes in LXR-agonist–treated trabecular meshwork cells. GDF-15 levels showed a twofold expression in the AH of patients with UG (n = 44) compared with controls (n = 24; P = 0.024) and increased with more anti-glaucoma eyedrops and glaucoma surgeries (P < 0.05). LXRα/β and GDF-15 were found in human outflow tissue and were up-regulated by lipopolysaccharide and CMV infection. In an experimental endotoxin uveitis model, GDF-15 levels were up-regulated by the treatment with LXR agonists and lipopolysaccharide. In human trabecular meshwork cells, LXR agonists triggered actin stress fiber formation and α-smooth muscle actin expression, both reduced by GDF-15 neutralization. These results suggest that the LXR–GDF-15 pathway contributes to profibrotic changes in UG and plays a role in disease pathogenesis.