Neutrophil elastase promotes interleukin-1β secretion from human coronary endothelium.
The endothelium is critically involved in the pathogenesis of atherosclerosis by producing pro-inflammatory mediators, including IL-1β. Coronary arteries from patients with ischemic heart disease express large amounts of IL-1β in the endothelium. However, the mechanism by which endothelial cells (ECs) release IL-1β remains to be elucidated. We investigated neutrophil elastase (NE), a potent serine protease detected in vulnerable areas of human carotid plaques, as a potential "trigger" for IL-1β processing and release. This study tested the hypothesis that NE potentiates the processing and release of IL-1β from human coronary endothelium. We found that NE cleaves the pro-isoform of IL-1β in ECs and causes significant secretion of bioactive IL-1β via extracellular vesicles. This release was attenuated significantly by inhibition of neutrophil elastase but not caspase-1. Transient increases in intracellular Ca(2+) levels were observed prior to secretion. Inside ECs, and after NE treatment only, IL-1β was detected within LAMP-1-positive multivesicular bodies. The released vesicles contained bioactive IL-1β. In vivo, in experimental atherosclerosis, NE was detected in mature atherosclerotic plaques, predominantly in the endothelium, alongside IL-1β. This study reveals a novel mechanistic link between NE expression in atherosclerotic plaques and concomitant pro-inflammatory bioactive IL-1β secretion from ECs. This could reveal additional potential anti-IL-1β therapeutic targets and provide further insights into the inflammatory process by which vascular disease develops.
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Mabruka
M
Alfaidi
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Heather
H
Wilson
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Marc
M
Daigneault
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Amanda
A
Burnett
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Victoria
V
Ridger
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Janet
J
Chamberlain
From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom s.francis@sheffield.ac.uk.
Sheila
S
Francis
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology; D004730:Endothelium, Vascular / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000378:metabolism
D001057:Apolipoproteins E; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D019272:Leukocyte Elastase; D002118:Calcium
IL-1; atherosclerosis; endothelium; extracellular vesicles; inflammation; neutrophil elastase