Abstract
Purpose :
In the pathogenesis of uveitic glaucoma, virus-induced trabeculitis is considered as a significant cause, markedly by a sudden increase in intraocular pressure (IOP) and relatively mild inflammation in the anterior chamber. In the previous proteome analyses of the aqueous humor derived from the CMV uveitic glaucoma patients using IPA analyses, we observed that the Liver X receptor (LXR) pathway is among the most prominently activated canonical pathways. Recent genome-wide association studies identified ATP binding cassette transporter A1 (ABCA1), the downstream molecule of LXR, as a candidate gene within a POAG susceptibility locus. Thus, we explored the role of LXR pathway in the etiology of glaucoma in association with ocular inflammation.
Methods :
Regulation of expression by external cues, and the distribution and secretion of LXR-ABCA1 by human trabecular meshwork (TM) primary cell cultures and aqueous humor derived from patients with uveitic glaucoma. The effects of LXR agonist were evaluated in the context of LPS-mediated inflammation in human TM and in a rat model of endotoxin-induced uveitis.
Results :
LXRα/β and ABCA1 were confirmed to be distributed throughout the conventional aqueous humor outflow pathway of the human eye. LXRα/β and ABCA1 were significantly increased in human TM cells in response to CMV infection and LPS. LXR agonists inhibited LPS induction of IL-1, IL-6, MCP-1, and ATX. In both LXRα/LXRβ knockdown cells, LXR agonist induced suppression was reversed, suggesting that such suppression is LXRα or LXRβ receptor mediated. In rat model, LXR agonist significantly reduced infiltrating cells and decreased the expression of proinflammatory cytokines, including TNF-alpha, IL-1, IL-6, MCP-1, NFkB2, and TGF-beta1 in iris and retina.
Conclusions :
In the conventional outflow tract, LXR-ABCA molecules were physiologically distributed, showing a robust induction in response to inflammatory insult. Moreover, the activation of LXR exhibited a potent anti-inflammatory effect, suggesting its physiological protective role in the glaucoma associated with ocular inflammation.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.