Regulation of monocyte activation by PPARα through interaction with the cGAS-STING pathway

Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-alpha (PPARα), has shown robust therapeutic effects on DR in type 2 diabetic patients. Here we found that PPARα levels were significantly down-regulated in monocytes from diabetic patients and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knock-out alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knock-out aggravated, monocyte activation in diabetes. PPARα knock-out impaired mitochondrial function, while increasing glycolysis in monocytes. PPARα knock-out increased cytosolic mitochondrial DNA release and activation of the cGAS-STING pathway in monocytes under diabetic conditions. STING knock-out or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knock-out. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.