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
Alfred A R Thompson
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
- Jody Rosenblatt, King's College London, United Kingdom
Publication history
- Received: August 9, 2019
- Accepted: October 15, 2019
- Accepted Manuscript published: October 15, 2019 (version 1)
- 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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