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The peroxisome proliferator-activated receptor-β/δ antagonist GSK0660 mitigates retinal cell inflammation and
Megan E Capozzi1, Sara R Savage2, Gary W McCollum3
1Department of Molecular Physiology and Biophysics, Vanderbilt University, USA.
Abstract:
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.
Insights
Inhibition of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) may treat diabetic retinopathy (DR). PPARβ/δ activation by free fatty acids drives inflammation in retinal cells, and blocking it reduces these damaging pathways.
Area of Science:
- Ophthalmology
- Molecular Biology
- Diabetology
Background:
- Diabetic retinopathy (DR) involves retinal cell damage from high blood sugar and free fatty acids.
- Free fatty acids can trigger Müller cells to release inflammatory cytokines, promoting retinal endothelial pathology.
- Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is implicated in DR pathogenesis, including angiogenesis and inflammation.
Purpose of the Study:
- To investigate the role of PPARβ/δ in mediating free fatty acid-induced inflammation in Müller cells and endothelial cells.
- To determine if inhibiting PPARβ/δ can mitigate inflammatory signaling in early DR pathology.
Main Methods:
- Utilized a PPARβ/δ inhibitor (GSK0660) in primary human Müller cells (HMC), human retinal microvascular endothelial cells (HRMEC), and mouse retina models.
- Analyzed the production of cytokines and chemokines in response to palmitic acid (PA) and PPARβ/δ inhibition.
Main Results:
- Palmitic acid activation of PPARβ/δ in HMC induced pro-angiogenic and inflammatory cytokines, acting as upstream signals.
- Endothelial cells (EC) transduced these signals, increasing chemokine release (CCL8, CXCL10) that promotes leukostasis.
- PPARβ/δ inhibition effectively reduced both upstream (Müller cell) and downstream (endothelial cell) inflammatory signaling.
Conclusions:
- PPARβ/δ plays a critical role in mediating inflammatory responses in both Müller cells and retinal endothelial cells in the context of DR.
- Inhibition of PPARβ/δ demonstrates potential as a therapeutic strategy for early diabetic retinopathy by dampening key inflammatory pathways.
