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
  • Animals
  • Apoptosis/physiology
  • ErbB Receptors/metabolism
  • Humans
  • Inflammation
  • Macrophages/metabolism
  • Mice
  • Neutrophils*
  • Protein Kinase Inhibitors
  • Proteome/metabolism
  • Quinolines
  • Zebrafish*
PubMed
35967296 Full text @ Front Immunol
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.
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