Abstract
Purpose :
Monocyte activation and adhesion to the retinal vasculature play a pathogenic role in diabetic retinopathy (DR). Two independent and prospective clinical studies reported that fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARα), has robust therapeutic effects on DR in type 2 diabetic patients. The purpose of this study was to explore the role of PPARα in monocyte activation.
Methods :
Flow cytometry was performed to measure PPARα levels in CD11b positive monocytes from diabetic human subjects, and type 1 and type 2 diabetic animal models. Monocyte adhesion, phagocytosis and migration were studied using endothelial cell-monocyte adhesion assay, phagocytosis assay and Transwell migration assay. The metabolic profile in monocytes was analyzed using a Seahorse Analyzer.
Results :
PPARα levels were down-regulated in monocytes from diabetic patients and animal models, correlating with monocyte activation, including increased adhesion, migration, and phagocytosis. Activation of PPARα by fenofibrate attenuated monocyte activation induced by diabetes or by oxidative stress in vitro. PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated, monocyte activation in diabetic conditions. PPARα knockout impaired mitochondrial function and increased cytosolic mitochondrial DNA release, leading to activation of the cyclic GMP–AMP (cGAS) and cyclic GMP–AMP receptor stimulator of interferon genes (STING) pathway in monocytes. STING knockout or inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout.
Conclusions :
PPARα regulates the activation of monocytes through metabolic reprogramming and interacts with the cGAS-STING pathway in monocytes, suggesting that PPARα in monocytes is a potential therapeutic target for DR.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.