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

Authors Jiang Y, Steinle JJ

Received 29 March 2019

Accepted for publication 9 May 2019

Published 12 June 2019 Volume 2019:12 Pages 153—159

DOI https://doi.org/10.2147/JIR.S210441

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Ning Quan


Youde Jiang, Jena J Steinle

Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA

Purpose: 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

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