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

Kristopher R Genschmer; Derek W Russell; Charitharth Lal; Tomasz Szul; Preston E Bratcher; Brett D Noerager; Mojtaba Abdul Roda; Xin Xu; Gabriel Rezonzew; Liliana Viera; Brian S Dobosh; Camilla Margaroli; Tarek H Abdalla; Robert W King; Carmel M McNicholas; J Michael Wells; Mark T Dransfield; Rabindra Tirouvanziam; Amit Gaggar; J Edwin Blalock

doi:10.1016/j.cell.2018.12.002

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

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

Authors

Kristopher R Genschmer¹, Derek W Russell¹, Charitharth Lal², Tomasz Szul³, Preston E Bratcher⁴, Brett D Noerager⁵, Mojtaba Abdul Roda³, Xin Xu⁶, Gabriel Rezonzew², Liliana Viera⁷, Brian S Dobosh⁸, Camilla Margaroli⁸, Tarek H Abdalla⁹, Robert W King⁹, Carmel M McNicholas¹⁰, J Michael Wells¹¹, Mark T Dransfield¹², Rabindra Tirouvanziam⁸, Amit Gaggar¹³, J Edwin Blalock¹⁴

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bronchoalveolar Lavage Fluid / cytology
Cells, Cultured
Exosomes / physiology*
Extracellular Matrix / metabolism
Female
Humans
Inflammation
Integrins
Leukocyte Elastase / metabolism
Lung / metabolism
Lung / physiopathology
Male
Mice
Mice, Inbred C57BL
Neutrophils / metabolism*
Neutrophils / physiology
Pulmonary Disease, Chronic Obstructive / physiopathology
alpha 1-Antitrypsin / metabolism

Substances

Integrins
alpha 1-Antitrypsin
Leukocyte Elastase

Abstract

Publication types

MeSH terms

Substances

Grants and funding