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

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

Cell, 2019-01, Vol.176 (1-2), p.113-126.e15 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung
Autor: Genschmer, Kristopher R. ; Russell, Derek W. ; Lal, Charitharth ; Szul, Tomasz ; Bratcher, Preston E. ; Noerager, Brett D. ; Abdul Roda, Mojtaba ; Xu, Xin ; Rezonzew, Gabriel ; Viera, Liliana ; Dobosh, Brian S. ; Margaroli, Camilla ; Abdalla, Tarek H. ; King, Robert W. ; McNicholas, Carmel M. ; Wells, J. Michael ; Dransfield, Mark T. ; Tirouvanziam, Rabindra ; Gaggar, Amit ; Blalock, J. Edwin
Assuntos: alpha 1-Antitrypsin - metabolism ; Animals ; BPD ; Bronchoalveolar Lavage Fluid - cytology ; Cells, Cultured ; COPD ; ELA-2 ; elastase ; exosomes ; Exosomes - physiology ; extracellular matrix ; Extracellular Matrix - metabolism ; extracellular vesicles ; Female ; Humans ; Inflammation ; Integrins ; Leukocyte Elastase - metabolism ; Lung - metabolism ; Lung - physiopathology ; lung disease ; Male ; Mice ; Mice, Inbred C57BL ; microparticles ; neutrophil ; Neutrophils - metabolism ; Neutrophils - physiology ; Pulmonary Disease, Chronic Obstructive - physiopathology
É parte de: Cell, 2019-01, Vol.176 (1-2), p.113-126.e15
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Author Contributions
Conceptualization, J.E.B., A.G., D.W.R., and K.R.G.; Methodology, D.W.R. and K.R.G.; Investigation, K.R.G., D.W.R., C.L., G.R., T.S., P.E.B., B.D.N., M.A.R., X.X., L.V., B.D., C.M., T.H.A., R.W.K., and C.M.M.; Resources, J.M.W., M.T.D., R.T., and L.V.; Writing-Original Draft, D.W.R. and K.R.G.; Writing-Review and Editing, J.E.B., A.G., J.M.W., and R.T.; Supervision, J.E.B. and A.G.; Funding Acquisition, J.E.B., A.G., R.T., J.M.W. and L.V.
Descrição: 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. [Display omitted] •Exosomes from activated, not quiescent, PMNs harbor surface α1AT-insensitive NE•Activated PMN exosomes bind ECM via MAC-1 and degrade ECM via NE•CD66b+/NE+ PMN exosomes cause emphysema and RVH when administered to mice•CD66b+/NE+ PMN exosomes reside in COPD patients and transfer a COPD phenotype to mice In chronic inflammatory lung disease, neutrophil-derived pathogenic exosomes bypass the pulmonary antiprotease barrier to promote extracellular matrix destruction.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

United States: Elsevier Inc

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