Neutrophil elastase contributes to the pathological vascular permeability characteristic of diabetic retinopathy.

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 wild-type 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.

• Authors: Haitao Liu, Emma M Lessieur, Aicha Saadane, Sarah I Lindstrom, Patricia R Taylor, Timothy S Kern
• Journal: Diabetologia (Diabetologia) Vol. 62 Issue 12 Pg. 2365-2374 (12 2019) ISSN: 1432-0428 [Electronic] Germany
• PMID: 31612267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Interleukin-17
• Leukocyte Elastase

Topics

• Animals
• Blood-Retinal Barrier (metabolism, pathology)
• Capillary Permeability (genetics)
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology)
• Diabetic Retinopathy (genetics, metabolism, pathology)
• Interleukin-17 (genetics, metabolism)
• Leukocyte Elastase (genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• Retina (metabolism, pathology)
• Retinal Vessels (metabolism, pathology)