Journal
CELL
Volume 176, Issue 1-2, Pages 113-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.12.002
Keywords
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Categories
Funding
- NHLBI, NIH
- Family Smoking Prevention and Tobacco Control Act
- UAB O'Brien Acute Kidney Injury Center [P30 DK079337]
- UAB Lung Health Center
- UAB Center for Free Radical Biology
- Comprehensive Cancer Center Core [P30 CA031148]
- NIH [P30 DK072482]
- CF Foundation Research Development Program grant
- Veteran's Affairs [I01BX001756]
- Nancy Dunlap Chair
- [R35HL135710]
- [R01HL077783]
- [R01HL114439]
- [R01HL110950]
- [R01HL126596]
- [R01HL102371]
- [R01HL126603]
- [K08HL123940]
- [T32HL105346-07]
- [T32 HL105346-05]
- [AHA17SDG32720009]
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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 alpha 1-antitrypsin (alpha 1AT). 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 alpha 1AT 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.
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