Taylor, S., Isobe, S., Cao, A. et al. (27 more authors) (2022) Endogenous retroviral elements generate pathologic neutrophils in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 206 (8). pp. 1019-1034. ISSN 1073-449X
Abstract
Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: Relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion and migration were assessed in neutrophils from pulmonary arterial hypertension patients and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension and we determined whether they produce pulmonary hypertension in mice. Measurements and Main Results: Neutrophils from pulmonary arterial hypertension patients produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated β1integrin and vinculin identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature that we related to an increase in human endogenous retrovirus k envelope protein. Transfection of human endogenous retrovirus k envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and interferon genes, whereas vinculin is increased by human endogenous retrovirus k dUTPase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus k envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 by the American Thoracic Society. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | antiviral agents; elafin; extracellular vesicles; leukocyte elastase; vinculin |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 22 Aug 2022 10:51 |
Last Modified: | 27 Jan 2023 15:55 |
Status: | Published |
Publisher: | American Thoracic Society |
Refereed: | Yes |
Identification Number: | 10.1164/rccm.202102-0446oc |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:189766 |