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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)449-458
Number of pages10
JournalThorax
Volume75
Issue number6
DOIs
Publication statusPublished - 1 Jun 2020
Externally publishedYes

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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  • Cite this

    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