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.

中文翻译：

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PPARα 通过与 cGAS-STING 通路相互作用调节单核细胞活化

单核细胞激活在糖尿病并发症如糖尿病视网膜病变 (DR) 中起重要作用。然而，糖尿病中单核细胞活化的调节仍然难以捉摸。非诺贝特是过氧化物酶体增殖物激活受体-α (PPARα) 的激动剂，对 2 型糖尿病患者的 DR 显示出强大的治疗效果。在这里，我们发现糖尿病患者和动物模型的单核细胞中 PPARα 水平显着下调，与单核细胞活化相关。非诺贝特减弱了糖尿病中的单核细胞活化，而单独敲除 PPARα 可诱导单核细胞活化。此外，单核细胞特异性 PPARα 过表达得到改善，而单核细胞特异性 PPARα 敲除加剧了糖尿病中的单核细胞活化。PPARα 敲除会损害线粒体功能，同时增加单核细胞的糖酵解。PPARα 敲除增加了糖尿病条件下单核细胞中细胞溶质线粒体 DNA 的释放和 cGAS-STING 通路的激活。STING 敲除或 STING 抑制剂减弱了由糖尿病或 PPARα 敲除诱导的单核细胞活化。这些观察结果表明，PPARα 通过代谢重编程和与 cGAS-STING 通路的相互作用负向调节单核细胞活化。