Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Diabetes. 2023 Jul 1;72(7):958-972. doi: 10.2337/db22-0654.
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-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα 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 PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.
单核细胞激活在糖尿病并发症中起着重要作用，如糖尿病视网膜病变 (DR)。然而，糖尿病中单核细胞激活的调节仍不清楚。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 具有显著的治疗作用。在这里，我们发现糖尿病患者和动物模型的单核细胞中 PPARα 水平显著下调，与单核细胞激活相关。非诺贝特可减轻糖尿病中的单核细胞激活，而单独敲除 PPARα 则会诱导单核细胞激活。此外，单核细胞特异性过表达 PPARα 可改善糖尿病中的单核细胞激活，而单核细胞特异性敲除 PPARα 则会加重其激活。PPARα 敲除会损害线粒体功能，同时增加单核细胞中的糖酵解。在糖尿病条件下，PPARα 敲除会增加细胞质线粒体 DNA 的释放和环鸟苷酸-腺苷酸合酶 (cGAS)-干扰素基因刺激物 (STING) 途径的激活。STING 敲除或 STING 抑制剂可减轻糖尿病或 PPARα 敲除引起的单核细胞激活。这些观察结果表明，PPARα 通过代谢重编程和与 cGAS-STING 途径的相互作用负调节单核细胞激活。
