Neutrophil elastase contributes to the pathological vascular permeability characteristic of diabetic retinopathy
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ARTICLE
Neutrophil elastase contributes to the pathological vascular permeability characteristic of diabetic retinopathy Haitao Liu 1,2 & Emma M. Lessieur 3 & Aicha Saadane 3 & Sarah I. Lindstrom 4 & Patricia R. Taylor 4,5 & Timothy S. Kern 3,5,6 Received: 14 April 2019 / Accepted: 31 July 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract Aims/hypothesis Levels of neutrophil elastase, a serine protease secreted by neutrophils, are elevated in diabetes. The purpose of this study was to determine whether neutrophil elastase (NE) contributes to the diabetes-induced increase in retinal vascular permeability in mice with streptozotocin-induced diabetes, and, if so, to investigate the potential role of IL-17 in this process. Methods In vivo, diabetes was induced in neutrophil elastase-deficient (Elane−/−), Il-17a−/− and wild-type mice. After 8 months of diabetes, Elane−/− mice and wild-type age-matched control mice were injected with FITC-BSA. Fluorescence microscopy was used to assess leakage of FITC-BSA from the retinal vasculature into the neural retina. The level of NE in Il-17a−/− diabetic retina and sera were determined by ELISA. In vitro, the effect of NE on the permeability and viability of human retinal endothelial cells and the expression of junction proteins and adhesion molecules were studied. Results Eight months of diabetes resulted in increased retinal vascular permeability and levels of NE in retina and plasma of wildtype animals. All of these abnormalities were significantly inhibited in mice lacking the elastase. The diabetes-induced increase in NE was inhibited in mice lacking IL-17. In vitro, NE increased retinal endothelial cell permeability, which was partially inhibited by a myeloid differentiation primary response 88 (MyD88) inhibitor, NF-κB inhibitor, and protease-activated receptor (PAR)2 inhibitor. NE degraded vascular endothelial-cadherin (VE-cadherin) in a concentration-dependent manner. Conclusions/interpretation IL-17 regulates NE expression in diabetes. NE contributes to vascular leakage in diabetic retinopathy, partially through activation of MyD88, NF-κB and PAR2 and degradation of VE-cadherin. Keywords Diabetic retinopathy . Elane . IL-17 . Neutrophil elastase . Vascular permeability
Abbreviations hREC
Human retinal endothelial cell
ICAM-1 INL
Intercellular adhesion molecule 1 Inner nuclear layer
Haitao Liu and Emma M. Lessieur contributed equally to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-019-04998-4) contains peer reviewed but unedited supplementary material, which is available to authorised users. * Timothy S. Kern [email protected] 1
2
3
Center for Translational Vision Research, Department of Ophthalmology, Gavin Herbert Eye Institute, School of Medicine, University of California-Irvine, 829 Health Sciences Rd. Gillespie Neuroscience Research Facility, Room 2107, Irvine, CA 92697, USA
4
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland,
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