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Published on: August 11, 2023
Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
Cayla D Ontko1, Megan E Capozzi2, Minjae J Kim3
1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. cayla.ontko@vanderbilt.edu.
Abstract:
Free fatty acid dysregulation in diabetics may elicit the release of inflammatory cytokines from Müller cells (MC), promoting the onset and progression of diabetic retinopathy (DR). Palmitic acid (PA) is elevated in the sera of diabetics and stimulates the production of the DR-relevant cytokines by MC, including IL-1β, which induces the production of itself and other inflammatory cytokines in the retina as well. In this study we propose that experimental elevation of cytochrome P450 epoxygenase (CYP)-derived epoxygenated fatty acids, epoxyeicosatrienoic acid (EET) and epoxydocosapentaenoic acid (EDP), will reduce PA- and IL-1β-induced MC inflammation. Broad-spectrum CYP inhibition by SKF-525a increased MC expression of inflammatory cytokines. Exogenous 11,12-EET and 19,20-EDP significantly decreased PA- and IL-1β-induced MC expression of IL-1β and IL-6. Both epoxygenated fatty acids significantly decreased IL-8 expression in IL-1β-induced MC and TNFα in PA-induced MC. Interestingly, 11,12-EET and 19,20-EDP significantly increased TNFα in IL-1β-treated MC. GSK2256294, a soluble epoxide hydrolase (sEH) inhibitor, significantly reduced PA- and IL-1β-stimulated MC cytokine expression. 11,12-EET and 19,20-EDP were also found to decrease PA- and IL-1β-induced NFκB-dependent transcriptional activity. These data suggest that experimental elevation of 11,12-EET and 19,20-EDP decreases MC inflammation in part by blocking NFκB-dependent transcription and may represent a viable therapeutic strategy for inhibition of early retinal inflammation in DR.
Insights
Elevating specific epoxygenated fatty acids, epoxyeicosatrienoic acid (EET) and epoxydocosapentaenoic acid (EDP), reduces inflammation in Müller cells (MC). This suggests a potential therapeutic strategy for diabetic retinopathy (DR).
Area of Science:
- Ophthalmology
- Endocrinology
- Molecular Biology
Background:
- Diabetic retinopathy (DR) is exacerbated by free fatty acid dysregulation and inflammatory cytokine release from Müller cells (MC).
- Palmitic acid (PA), elevated in diabetics, stimulates MCs to produce DR-relevant cytokines like IL-1β, promoting retinal inflammation.
Purpose of the Study:
- To investigate if experimentally elevating cytochrome P450 (CYP)-derived epoxygenated fatty acids, epoxyeicosatrienoic acid (EET) and epoxydocosapentaenoic acid (EDP), can mitigate PA- and IL-1β-induced MC inflammation.
Main Methods:
- Utilized broad-spectrum CYP inhibition (SKF-525a) and exogenous administration of 11,12-EET and 19,20-EDP to MCs.
- Assessed cytokine expression (IL-1β, IL-6, IL-8, TNFα) and NFκB-dependent transcriptional activity.
- Employed a soluble epoxide hydrolase (sEH) inhibitor (GSK2256294) to evaluate its effect on MC cytokine expression.
Main Results:
- Exogenous 11,12-EET and 19,20-EDP significantly decreased MC expression of IL-1β, IL-6, IL-8, and TNFα induced by PA or IL-1β.
- The sEH inhibitor GSK2256294 also reduced PA- and IL-1β-stimulated MC cytokine expression.
- Both EET and EDP significantly reduced NFκB-dependent transcriptional activity in PA- and IL-1β-treated MCs.
Conclusions:
- Experimental elevation of 11,12-EET and 19,20-EDP effectively reduces MC inflammation.
- This reduction is partly mediated by the blockade of NFκB-dependent transcription.
- These epoxygenated fatty acids represent a potential therapeutic strategy for inhibiting early-stage retinal inflammation in diabetic retinopathy.
