Diabetic retinopathy (DR) is triggered by retinal cell damage stimulated by the diabetic milieu, including increased levels of intraocular free fatty acids. Free fatty acids may serve as an initiator of inflammatory cytokine release from Müller cells, and the resulting cytokines are potent stimulators of retinal endothelial pathology, such as leukostasis, vascular permeability, and basement membrane thickening. Our previous studies have elucidated a role for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in promoting several steps in the pathologic cascade in DR, including angiogenesis and expression of inflammatory mediators. Furthermore, PPARβ/δ is a known target of lipid signaling, suggesting a potential role for this transcription factor in fatty acid-induced retinal inflammation. Therefore, we hypothesized that PPARβ/δ stimulates both the induction of inflammatory mediators by Müller cells as well the paracrine induction of leukostasis in endothelial cells (EC) by Müller cell inflammatory products. To test this, we used the PPARβ/δ inhibitor, GSK0660, in primary human Müller cells (HMC), human retinal microvascular endothelial cells (HRMEC) and mouse retina. We found that palmitic acid (PA) activation of PPARβ/δ in HMC leads to the production of pro-angiogenic and/or inflammatory cytokines that may constitute DR-relevant upstream paracrine inflammatory signals to EC and other retinal cells. Downstream, EC transduce these signals and increase their synthesis and release of chemokines such as CCL8 and CXCL10 that regulate leukostasis and other cellular events related to vascular inflammation in DR. Our results indicate that PPARβ/δ inhibition mitigates these upstream (MC) as well as downstream (EC) inflammatory signaling events elicited by metabolic stimuli and inflammatory cytokines. Therefore, our data suggest that PPARβ/δ inhibition is a potential therapeutic strategy against early DR pathology.

中文翻译：

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过氧化物酶体增殖物激活的受体-β/δ拮抗剂GSK0660减轻了视网膜细胞的炎症和白细胞停滞。

糖尿病性视网膜病（DR）是由糖尿病环境刺激的视网膜细胞损伤引发的，包括眼内游离脂肪酸水平升高。游离脂肪酸可能是从Müller细胞释放炎性细胞因子的引发剂，并且产生的细胞因子是视网膜内皮病理学的有效刺激物，例如白细胞停滞，血管通透性和基底膜增厚。我们以前的研究阐明了过氧化物酶体增殖物激活的受体β/δ（PPARβ/δ）在促进DR病理性级联反应的几个步骤中的作用，包括血管生成和炎症介质的表达。此外，PPARβ/δ是脂质信号转导的已知靶标，表明该转录因子在脂肪酸诱导的视网膜炎症中具有潜在作用。所以，我们假设PPARβ/δ既刺激Müller细胞诱导炎症介质的诱导，又刺激Müller细胞炎性产物对内皮细胞（EC）白内障的旁分泌诱导。为了测试这一点，我们在原代人Müller细胞（HMC），人视网膜微血管内皮细胞（HRMEC）和小鼠视网膜中使用了PPARβ/δ抑制剂GSK0660。我们发现，HMC中PPARβ/δ的棕榈酸（PA）活化导致促血管生成和/或炎性细胞因子的产生，这可能构成对EC和其他视网膜细胞与DR相关的上游旁分泌炎性信号。在下游，EC转导这些信号并增加其趋化因子（如CCL8和CXCL10）的合成和释放，这些趋化因子可调节白细胞停滞和与DR中与血管炎症相关的其他细胞事件。我们的结果表明，PPARβ/δ抑制可减轻由代谢刺激和炎性细胞因子引起的这些上游（MC）和下游（EC）炎症信号事件。因此，我们的数据表明，PPARβ/δ抑制是针对早期DR病理的潜在治疗策略。