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Cell. 2019 Jan 10;176(1-2):113-126.e15. doi: 10.1016/j.cell.2018.12.002.

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

Author information

1
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
2
Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Translational Research in Disordered and Normal Development Program, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
3
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
4
Department of Pediatrics, National Jewish Medical Center, Denver, CO 80206, USA.
5
University of Montevallo, Montevallo, AL 35115, USA.
6
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
7
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
8
Department of Pediatrics, Center of CF and Airways Disease Research, and Program in Immunology and Molecular Pathogenesis, Emory University, Atlanta, GA, USA.
9
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
10
Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
11
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Medical Service, Birmingham VA Medical Center Birmingham, AL 35294, USA.
12
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Medical Service, Birmingham VA Medical Center Birmingham, AL 35294, USA.
13
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Medical Service, Birmingham VA Medical Center Birmingham, AL 35294, USA.
14
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: jeblalock@uabmc.edu.

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.

KEYWORDS:

BPD; COPD; ELA-2; elastase; exosomes; extracellular matrix; extracellular vesicles; inflammation; lung disease; microparticles; neutrophil

PMID:
30633902
PMCID:
PMC6368091
[Available on 2020-01-10]
DOI:
10.1016/j.cell.2018.12.002

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