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Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation.
- Source :
-
ELife [Elife] 2019 Oct 15; Vol. 8. Date of Electronic Publication: 2019 Oct 15. - Publication Year :
- 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.<br />Competing Interests: AR, KH, KH, AT, HI, CT, DS, JR, NK, AR, KH, CT, IS, WZ, AM, MW, DD, SR, LP No competing interests declared, CS is an employee of GlaxoSmithKline Research and Development Ltd. The author declares no other competing interests exist.<br /> (© 2019, Rahman et al.)
- Subjects :
- Animal Fins injuries
Animal Fins pathology
Animals
Benzothiazoles administration & dosage
Cells, Cultured
Disease Models, Animal
ErbB Receptors antagonists & inhibitors
Humans
Mice
Protein Kinase Inhibitors administration & dosage
Treatment Outcome
Tyrphostins administration & dosage
Zebrafish
Inflammation pathology
Lung pathology
Neutrophils immunology
Pneumonia, Bacterial pathology
Pseudomonas Infections pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 31613219
- Full Text :
- https://doi.org/10.7554/eLife.50990