The peroxisome proliferator-activated receptor-β/δ antagonist GSK0660 mitigates retinal cell inflammation and leukostasis
The peroxisome proliferator-activated receptor-β/δ antagonist GSK0660 mitigates retinal cell inflammation and leukostasis
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DOI：
10.1016/j.exer.2019.107885
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发表时间：
2020-01-01
影响因子：
3.4
通讯作者：
Penn, John S.
中科院分区：
文献类型：
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作者：
Capozzi, Megan E.;Savage, Sara R.;Penn, John S.
糖尿病视网膜病变(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Muller细胞释放炎性细胞因子的启动者，由此产生的细胞因子是视网膜内皮细胞病理的有力刺激因素，如白细胞停滞、血管通透性和基底膜增厚。我们以前的研究已经阐明了PPARβ/Delta在促进DR病理级联中的几个步骤中的作用，包括血管生成和炎性介质的表达。此外，PPARβ/Delta是已知的脂质信号靶标，表明该转录因子在脂肪酸诱导的视网膜炎症中可能发挥作用。因此，我们假设PPARβ/Delta既能刺激Muller细胞诱导炎性介质，又能刺激Muller细胞炎性产物旁分泌诱导内皮细胞(EC)白血球淤滞。为了测试这一点，我们在原代人类Muller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/Delta抑制剂GSK0660。我们发现，棕榈酸(PA)激活HMC中PPARβ/Delta导致促血管生成和/或炎症细胞因子的产生，这些细胞因子可能构成与DR相关的上游旁分泌炎症信号，传递给EC和其他视网膜细胞。在下游，EC转导这些信号并增加它们的合成和释放，如CCL8和CXCL10，这些趋化因子调节白血病和其他与DR血管炎症相关的细胞事件。我们的结果表明，PPARβ/Delta抑制减轻了这些上游(MC)和下游(EC)由代谢刺激和炎症细胞因子引发的炎症信号事件。因此，我们的数据表明，抑制PPARβ/Delta是一种针对早期DR病理的潜在治疗策略。
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 Muller 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-beta/delta (PPAR beta/delta) in promoting several steps in the pathologic cascade in DR, including angiogenesis and expression of inflammatory mediators. Furthermore, PPAR beta/delta 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 PPAR beta/delta stimulates both the induction of inflammatory mediators by Muller cells as well the paracrine induction of leukostasis in endothelial cells (EC) by Muller cell inflammatory products. To test this, we used the PPAR beta/delta inhibitor, GSK0660, in primary human Muller cells (HMC), human retinal microvascular endothelial cells (HRMEC) and mouse retina. We found that palmitic acid (PA) activation of PPAR beta/delta 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 PPAR beta/delta 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 PPAR beta/delta inhibition is a potential therapeutic strategy against early DR pathology.