Regulation of Monocyte Activation by PPAR alpha 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 (PPAR alpha), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPAR alpha levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPAR alpha knockout alone induced monocyte activation. Furthermore, monocyte-specific PPAR alpha overexpression ameliorated, while monocyte-specific PPAR alpha knockout aggravated monocyte activation in diabetes. PPAR alpha knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPAR alpha knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPAR alpha knockout. These observations suggest that PPAR alpha negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.