Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation

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 cyto...

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Autores principales:	Cayla D. Ontko, Megan E. Capozzi, Minjae J. Kim, Gary W. McCollum, John S. Penn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/47a5c08f9bd747bdbb9357e26fe836ae
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spelling	oai:doaj.org-article:47a5c08f9bd747bdbb9357e26fe836ae2021-12-02T14:49:25ZCytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation10.1038/s41598-021-89000-12045-2322https://doaj.org/article/47a5c08f9bd747bdbb9357e26fe836ae2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89000-1https://doaj.org/toc/2045-2322Abstract 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.Cayla D. OntkoMegan E. CapozziMinjae J. KimGary W. McCollumJohn S. PennNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cayla D. Ontko Megan E. Capozzi Minjae J. Kim Gary W. McCollum John S. Penn Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
description	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.
format	article
author	Cayla D. Ontko Megan E. Capozzi Minjae J. Kim Gary W. McCollum John S. Penn
author_facet	Cayla D. Ontko Megan E. Capozzi Minjae J. Kim Gary W. McCollum John S. Penn
author_sort	Cayla D. Ontko
title	Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
title_short	Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
title_full	Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
title_fullStr	Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
title_full_unstemmed	Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation
title_sort	cytochrome p450-epoxygenated fatty acids inhibit müller glial inflammation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/47a5c08f9bd747bdbb9357e26fe836ae
work_keys_str_mv	AT cayladontko cytochromep450epoxygenatedfattyacidsinhibitmullerglialinflammation AT meganecapozzi cytochromep450epoxygenatedfattyacidsinhibitmullerglialinflammation AT minjaejkim cytochromep450epoxygenatedfattyacidsinhibitmullerglialinflammation AT garywmccollum cytochromep450epoxygenatedfattyacidsinhibitmullerglialinflammation AT johnspenn cytochromep450epoxygenatedfattyacidsinhibitmullerglialinflammation
_version_	1718389506708602880

Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation

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