Physiological activation of liver X receptor provides protection against ocular inflammation in uveitic glaucoma

Abstract

Virus-induced trabeculitis is considered a significant cause of uveitic glaucoma, being marked by a sudden increase in intraocular pressure and relatively mild inflammation in the anterior chamber of the eye. In previous proteome analyses of aqueous humor (AH) derived from Cytomegalovirus (CMV) uveitic glaucoma patients, we observed the liver X receptor (LXR) pathway to be among the most prominently activated canonical pathways. In the present study, we explored the role of the LXR pathway in the etiology of glaucoma in association with ocular inflammation. LXRα/β and ABCA1, the downstream targets of LXR, were distributed throughout the conventional AH outflow pathway of the human eye, and their increased levels in human trabecular meshwork cells in response to CMV infection and -lipopolysaccharide (LPS) treatment. Treatment with an LXR agonist (T091317) suppressed LPS-induced inflammation and this response was reversed under the deficiency of LXRα/LXRβ. Furthermore, in the rat endotoxin uveitis model, the LXR agonist significantly reduced infiltrating cells and expression of proinflammatory cytokines in the iris and retina. These results reveal upregulation of LXR-ABCA1 under inflammatory insult in the conventional AH outflow pathway, and activation of LXR exhibiting an anti-inflammatory effect, implying its essential physiological protective role in glaucoma associated with ocular inflammation.