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
-
- Animal Fins/injuries
- Animal Fins/pathology
- Animals
- Benzothiazoles/administration & dosage
- Cells, Cultured
- Disease Models, Animal
- ErbB Receptors/antagonists & inhibitors
- Humans
- Inflammation/pathology*
- Lung/pathology*
- Mice
- Neutrophils/immunology*
- Pneumonia, Bacterial/pathology*
- Protein Kinase Inhibitors/administration & dosage
- Pseudomonas Infections/pathology*
- Treatment Outcome
- Tyrphostins/administration & dosage
- Zebrafish
- PubMed
- 31613219 Full text @ Elife
Citation
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. (2019) Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation. eLIFE. 8.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping