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Mcl-1 protects eosinophils from apoptosis and exacerbates allergic airway inflammation
  1. Jennifer M Felton1,2,
  2. David A Dorward1,
  3. Jennifer A Cartwright1,
  4. Philippe MD Potey1,
  5. Calum T Robb1,
  6. Jingang Gui3,
  7. Ruth W Craig3,
  8. Jürgen Schwarze1,
  9. Christopher Haslett1,
  10. Rodger Duffin1,
  11. Ian Dransfield1,
  12. Christopher D Lucas1,
  13. Adriano G Rossi1
  1. 1 University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh BioQuarter, UK
  2. 2 Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Centre, Cincinnati, Ohio, USA
  3. 3 Department of Pharmacology and Toxicology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire, USA
  1. Correspondence to Dr Christopher D Lucas, University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh BioQuarter, EH16 4TJ, UK; christopher.lucas{at}ed.ac.uk

Abstract

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.

  • eosinophil biology
  • allergic lung disease
  • asthma mechanisms
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/thoraxjnl-2019-213204

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    Footnotes

    • CDL and AGR are joint senior authors.

    • Contributors JMF, CDL, DAD, JAC, PMDP, CTR and RD acquired, analysed and interpreted data. JG and RWC provided critical reagents. JMF, CDL, JS, CH, ID and AGR all made substantial contributions to the conception and design of the work and the interpretation of data. CDL, JMF, ID and AGR wrote the manuscript and all authors approved the final version.

    • Funding The authors acknowledge funding from the UK Medical Research Council (MR/K013386/1: AGR, CH, RD and JMF), the Wellcome Trust (206566/Z/17/Z, CDL; 108906/Z/15/Z, JAC) and a Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (1S2-101/02: CDL).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.