Abstract
Cytomegalovirus (CMV)-induced anterior uveitis is linked to increased intraocular pressure (IOP), suggesting pro-fibrotic 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 they have a role in increased IOP remained unelucidated. Herein, we explored the LXR pathway's role in AH outflow in UG. Global transcriptional analysis revealed that LXR activation primarily induces TGF-β signaling, with GDF-15, a growth factor in the TGF-β superfamily, being one of the most upregulated genes in LXR-agonist-treated trabecular meshwork (TM) cells. GDF-15 levels showed a two-fold expression in the AH of UG patients (n=44) compared to 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 upregulated by LPS and CMV infection. In an experimental endotoxin uveitis model, GDF-15 levels were up-regulated by the treatment with LXR agonists and LPS. In human TM cells, LXR agonists triggered actin stress fiber formation and α-SMA expression, both reduced by GDF neutralization. These results suggest that the LXR-GDF-15 pathway contributes to pro-fibrotic changes in UG and plays a role in disease pathogenesis.
Published Version
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