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