PUBLICATION
The EGFR/ErbB inhibitor neratinib modifies the neutrophil phosphoproteome and promotes apoptosis and clearance by airway macrophages
- Authors
- Herman, K.D., Wright, C.G., Marriott, H.M., McCaughran, S.C., Bowden, K.A., Collins, M.O., Renshaw, S.A., Prince, L.R.
- ID
- ZDB-PUB-220816-2
- Date
- 2022
- Source
- Frontiers in immunology 13: 956991 (Journal)
- Registered Authors
- Renshaw, Steve A.
- Keywords
- COPD, efferocytosis, inflammation, mouse lung injury model, neutrophil, neutrophil apoptosis, zebrafish
- MeSH Terms
-
- Zebrafish*
- Mice
- Neutrophils*
- ErbB Receptors/metabolism
- Protein Kinase Inhibitors
- Inflammation
- Animals
- Humans
- Apoptosis/physiology
- Macrophages/metabolism
- Proteome/metabolism
- Quinolines
- PubMed
- 35967296 Full text @ Front Immunol
Citation
Herman, K.D., Wright, C.G., Marriott, H.M., McCaughran, S.C., Bowden, K.A., Collins, M.O., Renshaw, S.A., Prince, L.R. (2022) The EGFR/ErbB inhibitor neratinib modifies the neutrophil phosphoproteome and promotes apoptosis and clearance by airway macrophages. Frontiers in immunology. 13:956991.
Abstract
Dysregulated neutrophilic inflammation can be highly destructive in chronic inflammatory diseases due to prolonged neutrophil lifespan and continual release of histotoxic mediators in inflamed tissues. Therapeutic induction of neutrophil apoptosis, an immunologically silent form of cell death, may be beneficial in these diseases, provided that the apoptotic neutrophils are efficiently cleared from the tissue. Previous research in our group identified ErbB inhibitors as able to induce neutrophil apoptosis and reduce neutrophilic inflammation both in vitro and in vivo. Here, we extend that work using a clinical ErbB inhibitor, neratinib, which has the potential to be repurposed in inflammatory diseases. We show that neratinib reduces neutrophilic migration o an inflammatory site in zebrafish larvae. Neratinib upregulates efferocytosis and reduces the number of persisting neutrophil corpses in mouse models of acute, but not chronic, lung injury, suggesting that the drug may have therapeutic benefits in acute inflammatory settings. Phosphoproteomic analysis of human neutrophils shows that neratinib modifies the phosphorylation of proteins regulating apoptosis, migration, and efferocytosis. This work identifies a potential mechanism for neratinib in treating acute lung inflammation by upregulating the clearance of dead neutrophils and, through examination of the neutrophil phosphoproteome, provides important insights into the mechanisms by which this may be occurring.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping