Edinburgh Research Explorer

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Research output: Contribution to journalArticle

  • Atiqur Rahman
  • Katherine M Henry
  • Kimberly D Herman
  • Alfred Ar Thompson
  • Hannah M Isles
  • Claudia Tulotta
  • David Sammut
  • Julien Jy Rougeot
  • Nika Khoshaein
  • Abigail E Reese
  • Kathryn Higgins
  • Caroline Tabor
  • Ian Sabroe
  • William J Zuercher
  • Caroline O Savage
  • Annemarie H Meijer
  • Moira Kb Whyte
  • David H Dockrell
  • Stephen A Renshaw
  • Lynne R Prince

Related Edinburgh Organisations

Open Access permissions

Open

Documents

  • Download as Adobe PDF

    Rights statement: Copyright Rahman et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

    Final published version, 3.04 MB, PDF document

    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
JournaleLIFE
Volume8
DOIs
Publication statusPublished - 15 Oct 2019

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.

Download statistics

No data available

ID: 131463650