PUBLICATION

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Authors
Rahman, A., Henry, K.M., Herman, K.D., Thompson, A.A.R., Isles, H.M., Tulotta, C., Sammut, D., Rougeot, J.J., Khoshaein, N., Reese, A.E., Higgins, K., Tabor, C., Sabroe, I., Zuercher, W.J., Savage, C.O., Meijer, A.H., Whyte, M.K., Dockrell, D.H., Renshaw, S.A., Prince, L.R.
ID
ZDB-PUB-191016-7
Date
2019
Source
eLIFE   8: (Journal)
Registered Authors
Henry, Katherine, Meijer, Annemarie H., Renshaw, Steve A., Rougeot, Julien
Keywords
human, immunology, inflammation, mouse, zebrafish
MeSH Terms
  • Protein Kinase Inhibitors/administration & dosage
  • Animals
  • Pneumonia, Bacterial/pathology*
  • Treatment Outcome
  • Mice
  • Lung/pathology*
  • Tyrphostins/administration & dosage
  • Benzothiazoles/administration & dosage
  • Inflammation/pathology*
  • Neutrophils/immunology*
  • Pseudomonas Infections/pathology*
  • Disease Models, Animal
  • Cells, Cultured
  • Humans
  • ErbB Receptors/antagonists & inhibitors
  • Zebrafish
  • Animal Fins/injuries
  • Animal Fins/pathology
(all 18)
PubMed
31613219 Full text @ Elife
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.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
i114TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    egfraCRISPR3-egfraCRISPR
    erbb2CRISPR1-erbb2CRISPR
    tyrCRISPR1-tyrCRISPR
    1 - 3 of 3
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    Fish
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    GFPEFGGFP
    1 - 1 of 1
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    Mapping
    No data available