Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung

• Type of Material: Article
• Authors: K. R. Genschmer, University of Alabama Birmingham; D. W. Russell, University of Alabama Birmingham; C. Lal, University of Alabama Birmingham; T Szul, University of Alabama Birmingham; P. E. Bratcher, National Jewish Medical Center; B. D. Noerager, University of Montevallo; M. Abdul Roda, University of Alabama Birmingham; X. Xu, University of Alabama Birmingham; G. Rezonzew, University of Alabama Birmingham; L. Viera, University of Alabama Birmingham; B. S. Dobosh, Emory University; C. Margaroli, Emory University; T. H. Abdalla, University of Alabama Birmingham; R. W. King, University of Alabama Birmingham; C. M. McNicholas, University of Alabama Birmingham; J. M. Wells, University of Alabama Birmingham; M. T. Dransfield, University of Alabama Birmingham; Rabindra Tirouvanziam, Emory University; A. Gaggar, University of Alabama Birmingham; J. E. Blalock, University of Alabama Birmingham
• Language: English
• Date: 2019-01-10
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2018.12.002
• Title of Journal or Parent Work: Cell
• Volume: 176
• Issue: 1-2
• Start Page: 113
• End Page: +
• Grant/Funding Information: The Targeted Metabolomics and Proteomics Laboratory supported in part from the UAB O’Brien Acute Kidney Injury Center (P30 DK079337), the UAB Lung Health Center and the UAB Center for Free Radical Biology and the UAB Heflin Center for Genomic Science supported in part from the Comprehensive Cancer Center Core grant P30 CA031148.; Research reported in this publication was supported by the NHLBI, NIH, and the Family Smoking Prevention and Tobacco Control Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.; This study was supported by: R35HL135710, R01HL077783, R01HL114439, R01HL110950 to JEB, R01HL126596 to JEB and AG, R01 HL102371 to AG, R01HL126603 to RT, K08HL123940 to JMW, T32HL105346–07 to DWR and T32 HL105346–05 to KRG; AHA-17SDG32720009 to CL; Veteran’s Affairs: I01BX001756 to AG; Nancy Dunlap Chair to JEB.
• Keywords: Pathway; Science & Technology; Biochemistry & Molecular Biology; Smoke-induced emphysema; Cell Biology; CATHEPSIN-G; Mice; Neutrophil elastase; Life Sciences & Biomedicine; Specificity; ALPHA(M)BETA(2); Mechanism; Baboon model; Inhibitor
• Research Categories: Chemistry, Biochemistry; Biology, Cell; Biology, Molecular

Abstract

Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63+/CD66b+ nanovesicles acquire surface-bound neutrophil elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to α1-antitrypsin (α1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and α1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia [BPD]). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.