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Published on: June 7, 2018
Neutrophil elastase promotes interleukin-1β secretion from human coronary endothelium
Mabruka Alfaidi1, Heather Wilson1, Marc Daigneault1
1From the Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Insights
Neutrophil elastase (NE) triggers the release of inflammatory interleukin-1 beta (IL-1β) from endothelial cells via extracellular vesicles. This discovery offers new therapeutic targets for atherosclerosis and vascular disease.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Endothelial Cell Biology
Background:
- Endothelium plays a key role in atherosclerosis pathogenesis by releasing pro-inflammatory mediators like IL-1β.
- High levels of IL-1β are found in the endothelium of coronary arteries from patients with ischemic heart disease.
- The precise mechanism of IL-1β release from endothelial cells is not fully understood.
Purpose of the Study:
- To investigate the role of neutrophil elastase (NE) in processing and releasing IL-1β from human coronary endothelium.
- To test the hypothesis that NE potentiates IL-1β processing and release.
Main Methods:
- Investigated NE's effect on pro-IL-1β processing in endothelial cells (ECs).
- Assessed IL-1β secretion via extracellular vesicles.
- Utilized NE inhibition and monitored intracellular Ca(2+) levels.
- Examined IL-1β localization within ECs and in vivo atherosclerotic plaques.
Main Results:
- NE cleaves pro-IL-1β in ECs, leading to bioactive IL-1β secretion via extracellular vesicles.
- NE inhibition significantly reduced IL-1β release, while caspase-1 inhibition did not.
- Increased intracellular Ca(2+) preceded IL-1β secretion.
- NE treatment resulted in IL-1β localization within LAMP-1-positive multivesicular bodies in ECs.
- Released extracellular vesicles contained bioactive IL-1β.
- In vivo, NE and IL-1β were co-localized in the endothelium of atherosclerotic plaques.
Conclusions:
- NE acts as a trigger for the processing and release of bioactive IL-1β from endothelial cells through extracellular vesicles.
- This NE-dependent pathway represents a novel mechanism linking NE in atherosclerotic plaques to endothelial inflammation.
- Findings suggest potential new therapeutic strategies targeting NE or IL-1β secretion in vascular disease.
Abstract:
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.
