Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis

Zivile Useckaite; Mark P. Ward; Anne Trappe; Rebecca Reilly; Jenny Lennon; Holly Davage; David Matallanas; Hilary Cassidy; Eugene T. Dillon; Kiva Brennan; Sarah L. Doyle; Suzanne Carter; Seamas Donnelly; Barry Linnane; Edward F. McKone; Paul McNally; Judith A. Coppinger

doi:10.1136/thoraxjnl-2019-214027

Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis

Zivile Useckaite, Mark P. Ward, Anne Trappe, Rebecca Reilly, Jenny Lennon, Holly Davage, David Matallanas, Hilary Cassidy, Eugene T. Dillon, Kiva Brennan, Sarah L. Doyle, Suzanne Carter, Seamas Donnelly, Barry Linnane, Edward F. McKone, Paul McNally, Judith A. Coppinger

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Abstract

Rationale Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene form the basis of cystic fibrosis (CF). There remains an important knowledge gap in CF as to how diminished CFTR activity leads to the dominant inflammatory response within CF airways. Objectives To investigate if extracellular vesicles (EVs) contribute to inflammatory signalling in CF. Methods EVs released from CFBE41o-, CuFi-5, 16HBE14o- and NuLi-1 cells were characterised by nanoparticle tracking analysis (NTA). EVs isolated from bronchoalveolar lavage fluid (BALF) from 30 people with CF (PWCF) were analysed by NTA and mass spectrometry and compared with controls. Neutrophils were isolated from the blood of 8 PWCF to examine neutrophil migration in the presence of CFBE41o- EVs. Results A significantly higher level of EVs were released from CFBE41o- (p<0.0001) and CuFi-5 (p=0.0209) relative to control cell lines. A significantly higher level of EVs were detected in BALF of PWCF, in three different age groups relative to controls (p=0.01, 0.001, 0.002). A significantly lower level of EVs were released from CFBE41o- (p<0.001) and CuFi-5 (p=0.0002) cell lines treated with CFTR modulators. Significant changes in the protein expression of 126 unique proteins was determined in EVs obtained from the BALF of PWCF of different age groups (p<0.001-0.05). A significant increase in chemotaxis of neutrophils derived from PWCF was observed in the presence of CFBE41o EVs (p=0.0024) compared with controls. Conclusion This study demonstrates that EVs are produced in CF airway cells, have differential protein expression at different ages and drive neutrophil recruitment in CF.

Original language	English
Pages (from-to)	449-458
Number of pages	10
Journal	Thorax
Volume	75
Issue number	6
DOIs	https://doi.org/10.1136/thoraxjnl-2019-214027
Publication status	Published - 1 Jun 2020
Externally published	Yes

Bibliographical note

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Keywords

Cystic fibrosis
Neutrophil biology
Paediatric lung disaese

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useckaite_Increased__P2020Final published version, 4.18 MBLicence: CC BY

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Useckaite, Z., Ward, M. P., Trappe, A., Reilly, R., Lennon, J., Davage, H., Matallanas, D., Cassidy, H., Dillon, E. T., Brennan, K., Doyle, S. L., Carter, S., Donnelly, S., Linnane, B., McKone, E. F., McNally, P., & Coppinger, J. A. (2020). Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis. Thorax, 75(6), 449-458. https://doi.org/10.1136/thoraxjnl-2019-214027

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title = "Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis",

abstract = "Rationale Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene form the basis of cystic fibrosis (CF). There remains an important knowledge gap in CF as to how diminished CFTR activity leads to the dominant inflammatory response within CF airways. Objectives To investigate if extracellular vesicles (EVs) contribute to inflammatory signalling in CF. Methods EVs released from CFBE41o-, CuFi-5, 16HBE14o- and NuLi-1 cells were characterised by nanoparticle tracking analysis (NTA). EVs isolated from bronchoalveolar lavage fluid (BALF) from 30 people with CF (PWCF) were analysed by NTA and mass spectrometry and compared with controls. Neutrophils were isolated from the blood of 8 PWCF to examine neutrophil migration in the presence of CFBE41o- EVs. Results A significantly higher level of EVs were released from CFBE41o- (p<0.0001) and CuFi-5 (p=0.0209) relative to control cell lines. A significantly higher level of EVs were detected in BALF of PWCF, in three different age groups relative to controls (p=0.01, 0.001, 0.002). A significantly lower level of EVs were released from CFBE41o- (p<0.001) and CuFi-5 (p=0.0002) cell lines treated with CFTR modulators. Significant changes in the protein expression of 126 unique proteins was determined in EVs obtained from the BALF of PWCF of different age groups (p<0.001-0.05). A significant increase in chemotaxis of neutrophils derived from PWCF was observed in the presence of CFBE41o EVs (p=0.0024) compared with controls. Conclusion This study demonstrates that EVs are produced in CF airway cells, have differential protein expression at different ages and drive neutrophil recruitment in CF.",

keywords = "Cystic fibrosis, Neutrophil biology, Paediatric lung disaese",

author = "Zivile Useckaite and Ward, {Mark P.} and Anne Trappe and Rebecca Reilly and Jenny Lennon and Holly Davage and David Matallanas and Hilary Cassidy and Dillon, {Eugene T.} and Kiva Brennan and Doyle, {Sarah L.} and Suzanne Carter and Seamas Donnelly and Barry Linnane and McKone, {Edward F.} and Paul McNally and Coppinger, {Judith A.}",

note = "This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.",

year = "2020",

month = jun,

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doi = "10.1136/thoraxjnl-2019-214027",

language = "English",

volume = "75",

pages = "449--458",

journal = "Thorax",

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Useckaite, Z, Ward, MP, Trappe, A, Reilly, R, Lennon, J, Davage, H, Matallanas, D, Cassidy, H, Dillon, ET, Brennan, K, Doyle, SL, Carter, S, Donnelly, S, Linnane, B, McKone, EF, McNally, P & Coppinger, JA 2020, 'Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis', Thorax, vol. 75, no. 6, pp. 449-458. https://doi.org/10.1136/thoraxjnl-2019-214027

TY - JOUR

T1 - Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis

AU - Useckaite, Zivile

AU - Ward, Mark P.

AU - Trappe, Anne

AU - Reilly, Rebecca

AU - Lennon, Jenny

AU - Davage, Holly

AU - Matallanas, David

AU - Cassidy, Hilary

AU - Dillon, Eugene T.

AU - Brennan, Kiva

AU - Doyle, Sarah L.

AU - Carter, Suzanne

AU - Donnelly, Seamas

AU - Linnane, Barry

AU - McKone, Edward F.

AU - McNally, Paul

AU - Coppinger, Judith A.

N1 - This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Rationale Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene form the basis of cystic fibrosis (CF). There remains an important knowledge gap in CF as to how diminished CFTR activity leads to the dominant inflammatory response within CF airways. Objectives To investigate if extracellular vesicles (EVs) contribute to inflammatory signalling in CF. Methods EVs released from CFBE41o-, CuFi-5, 16HBE14o- and NuLi-1 cells were characterised by nanoparticle tracking analysis (NTA). EVs isolated from bronchoalveolar lavage fluid (BALF) from 30 people with CF (PWCF) were analysed by NTA and mass spectrometry and compared with controls. Neutrophils were isolated from the blood of 8 PWCF to examine neutrophil migration in the presence of CFBE41o- EVs. Results A significantly higher level of EVs were released from CFBE41o- (p<0.0001) and CuFi-5 (p=0.0209) relative to control cell lines. A significantly higher level of EVs were detected in BALF of PWCF, in three different age groups relative to controls (p=0.01, 0.001, 0.002). A significantly lower level of EVs were released from CFBE41o- (p<0.001) and CuFi-5 (p=0.0002) cell lines treated with CFTR modulators. Significant changes in the protein expression of 126 unique proteins was determined in EVs obtained from the BALF of PWCF of different age groups (p<0.001-0.05). A significant increase in chemotaxis of neutrophils derived from PWCF was observed in the presence of CFBE41o EVs (p=0.0024) compared with controls. Conclusion This study demonstrates that EVs are produced in CF airway cells, have differential protein expression at different ages and drive neutrophil recruitment in CF.

AB - Rationale Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene form the basis of cystic fibrosis (CF). There remains an important knowledge gap in CF as to how diminished CFTR activity leads to the dominant inflammatory response within CF airways. Objectives To investigate if extracellular vesicles (EVs) contribute to inflammatory signalling in CF. Methods EVs released from CFBE41o-, CuFi-5, 16HBE14o- and NuLi-1 cells were characterised by nanoparticle tracking analysis (NTA). EVs isolated from bronchoalveolar lavage fluid (BALF) from 30 people with CF (PWCF) were analysed by NTA and mass spectrometry and compared with controls. Neutrophils were isolated from the blood of 8 PWCF to examine neutrophil migration in the presence of CFBE41o- EVs. Results A significantly higher level of EVs were released from CFBE41o- (p<0.0001) and CuFi-5 (p=0.0209) relative to control cell lines. A significantly higher level of EVs were detected in BALF of PWCF, in three different age groups relative to controls (p=0.01, 0.001, 0.002). A significantly lower level of EVs were released from CFBE41o- (p<0.001) and CuFi-5 (p=0.0002) cell lines treated with CFTR modulators. Significant changes in the protein expression of 126 unique proteins was determined in EVs obtained from the BALF of PWCF of different age groups (p<0.001-0.05). A significant increase in chemotaxis of neutrophils derived from PWCF was observed in the presence of CFBE41o EVs (p=0.0024) compared with controls. Conclusion This study demonstrates that EVs are produced in CF airway cells, have differential protein expression at different ages and drive neutrophil recruitment in CF.

KW - Cystic fibrosis

KW - Neutrophil biology

KW - Paediatric lung disaese

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U2 - 10.1136/thoraxjnl-2019-214027

DO - 10.1136/thoraxjnl-2019-214027

M3 - Article

C2 - 32265339

AN - SCOPUS:85083279637

SN - 0040-6376

VL - 75

SP - 449

EP - 458

JO - Thorax

JF - Thorax

IS - 6

ER -

Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis

Abstract

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Keywords

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