Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells

Youde Jiang, Jena J SteinleDepartment of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USAPurpose: Inflammation has been strongly associated with retinal damage in diseases such as diabetic retinopathy. Several studies have reported that high...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jiang Y, Steinle JJ
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	inflammasome NLRP3 PKR retinal endothelial cells Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/de5c849afd984451972265bd3eae937e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:de5c849afd984451972265bd3eae937e
record_format	dspace
spelling	oai:doaj.org-article:de5c849afd984451972265bd3eae937e2021-12-02T03:06:44ZEpac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells1178-7031https://doaj.org/article/de5c849afd984451972265bd3eae937e2019-06-01T00:00:00Zhttps://www.dovepress.com/epac1-inhibits-pkr-to-reduce-nlrp3-inflammasome-proteins-in-retinal-en-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Youde Jiang, Jena J SteinleDepartment of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USAPurpose: Inflammation has been strongly associated with retinal damage in diseases such as diabetic retinopathy. Several studies have reported that high glucose exposure induces damage to the retinal vasculature. We and others have shown that high glucose can activate the NOD-like receptor family, pyrin domain containing family member 3 (NLRP3) pathway, leading to increased levels of cleaved caspase 1 and IL-1β to activate a number of inflammatory pathways in the retina.Methods: We used retinal endothelial cells grown in normal (5 mM) or high (25 mM) glucose or retinal lysates from endothelial cell-specific knockout mice for exchange protein activated by cAMP 1 (Epac1). Human recombinant protein kinase R (PKR) or C16, a PKR inhibitor, was used on the cells to dissect PKR and NLRP3 signaling.Results: Using retinal endothelial cells (REC) in high glucose and whole retinal lysates from endothelial cell-specific knockout of Epac1, we demonstrate that Epac1 regulates PKR phosphorylation. Using an Epac1 agonist or PKR inhibition with C16, we demonstrated that loss of PKR resulted in reduced NLRP3, cleaved caspase 1, and IL-1β levels. Furthermore, despite the addition of recombinant human PKR, Epac1 was still able to significantly reduce NLRP3 signaling.Conclusion: Overall, these studies demonstrated that PKR regulates the NLRP3 inflammasome in REC, and that Epac1 inhibition of PKR can reduce activation of the NLRP3 inflammasome.Keywords: inflammasome, NLRP3, PKR, retinal endothelial cellsJiang YSteinle JJDove Medical PressarticleinflammasomeNLRP3PKRretinal endothelial cellsPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 12, Pp 153-159 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	inflammasome NLRP3 PKR retinal endothelial cells Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	inflammasome NLRP3 PKR retinal endothelial cells Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Jiang Y Steinle JJ Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells
description	Youde Jiang, Jena J SteinleDepartment of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USAPurpose: Inflammation has been strongly associated with retinal damage in diseases such as diabetic retinopathy. Several studies have reported that high glucose exposure induces damage to the retinal vasculature. We and others have shown that high glucose can activate the NOD-like receptor family, pyrin domain containing family member 3 (NLRP3) pathway, leading to increased levels of cleaved caspase 1 and IL-1β to activate a number of inflammatory pathways in the retina.Methods: We used retinal endothelial cells grown in normal (5 mM) or high (25 mM) glucose or retinal lysates from endothelial cell-specific knockout mice for exchange protein activated by cAMP 1 (Epac1). Human recombinant protein kinase R (PKR) or C16, a PKR inhibitor, was used on the cells to dissect PKR and NLRP3 signaling.Results: Using retinal endothelial cells (REC) in high glucose and whole retinal lysates from endothelial cell-specific knockout of Epac1, we demonstrate that Epac1 regulates PKR phosphorylation. Using an Epac1 agonist or PKR inhibition with C16, we demonstrated that loss of PKR resulted in reduced NLRP3, cleaved caspase 1, and IL-1β levels. Furthermore, despite the addition of recombinant human PKR, Epac1 was still able to significantly reduce NLRP3 signaling.Conclusion: Overall, these studies demonstrated that PKR regulates the NLRP3 inflammasome in REC, and that Epac1 inhibition of PKR can reduce activation of the NLRP3 inflammasome.Keywords: inflammasome, NLRP3, PKR, retinal endothelial cells
format	article
author	Jiang Y Steinle JJ
author_facet	Jiang Y Steinle JJ
author_sort	Jiang Y
title	Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells
title_short	Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells
title_full	Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells
title_fullStr	Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells
title_full_unstemmed	Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells
title_sort	epac1 inhibits pkr to reduce nlrp3 inflammasome proteins in retinal endothelial cells
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/de5c849afd984451972265bd3eae937e
work_keys_str_mv	AT jiangy epac1inhibitspkrtoreducenlrp3inflammasomeproteinsinretinalendothelialcells AT steinlejj epac1inhibitspkrtoreducenlrp3inflammasomeproteinsinretinalendothelialcells
_version_	1718401950263803904

Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells

Ejemplares similares