1. Immunology and Inflammation
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Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

  1. Atiqur Rahman
  2. Katherine M Henry
  3. Kimberly D Herman
  4. Alfred A R Thompson
  5. Hannah M Isles
  6. Claudia Tulotta
  7. David Sammut
  8. Julien JY Rougeot
  9. Nika Khoshaein
  10. Abigail E Reese
  11. Kathryn Higgins
  12. Caroline Tabor
  13. Ian Sabroe
  14. William J Zuercher
  15. Caroline O Savage
  16. Annemarie H Meijer
  17. Moira KB Whyte
  18. David H Dockrell
  19. Stephen A Renshaw
  20. Lynne R Prince  Is a corresponding author
  1. University of Sheffield, United Kingdom
  2. Leiden University, Netherlands
  3. University of North Carolina at Chapel Hill, United States
  4. GlaxoSmithKline Research and Development Ltd, United Kingdom
  5. University of Edinburgh, United Kingdom
Research Article
  • Cited 9
  • Views 2,975
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Cite this article as: eLife 2019;8:e50990 doi: 10.7554/eLife.50990

Abstract

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Atiqur Rahman

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Katherine M Henry

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0554-2063
  3. Kimberly D Herman

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Alfred A R Thompson

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0717-4551
  5. Hannah M Isles

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Claudia Tulotta

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. David Sammut

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Julien JY Rougeot

    Institute of Biology, Leiden University, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Nika Khoshaein

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Abigail E Reese

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Kathryn Higgins

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Caroline Tabor

    The Bateson Centre, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Ian Sabroe

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. William J Zuercher

    UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Caroline O Savage

    Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline Research and Development Ltd, Stevenage, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Annemarie H Meijer

    Institute of Biology, Leiden University, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  17. Moira KB Whyte

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. David H Dockrell

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Stephen A Renshaw

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1790-1641
  20. Lynne R Prince

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    For correspondence
    L.r.prince@sheffield.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6133-9372

Funding

Commonwealth Foundation

  • Atiqur Rahman

Medical Research Council (MR/M004864/1)

  • Stephen A Renshaw

Medical Research Council (G0700091)

  • Stephen A Renshaw

European Commission (PITG-GA-2011-289209)

  • Julien JY Rougeot
  • Annemarie H Meijer

SGC

  • William J Zuercher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Zebrafish were raised and maintained according to standard protocols in UK Home Office approved aquaria in the Bateson Centre at the University of Sheffield, according to institutional guidelines. All work involving mice was performed in accordance with the Animal (Scientific procedures) Act 1986 and has been approved by the Animal welfare and ethical review body at University of Sheffield. Work was carried out under procedure project license 40/3726. All animals were checked prior to the start of experiments by competent personal licensees (PIL), and were deemed to be fit and well before the start of experiments.

Human subjects: Peripheral blood of healthy subjects and COPD patients was taken following informed consent and in compliance with the guidelines of the South Sheffield Research Ethics Committee (for young healthy subjects; reference number: STH13927) and the National Research Ethics Service (NRES) Committee Yorkshire and the Humber (for COPD and age-matched healthy subjects; reference number: 10/H1016/25).

Reviewing Editor

  1. Jody Rosenblatt, King's College London, United Kingdom

Publication history

  1. Received: August 9, 2019
  2. Accepted: October 15, 2019
  3. Accepted Manuscript published: October 15, 2019 (version 1)
  4. Version of Record published: November 8, 2019 (version 2)

Copyright

© 2019, Rahman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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