¬The EGFR/ErbB inhibitor neratinib promotes apoptosis and clearance by airway macrophages

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. Inducing 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. Our previous research identified ErbB inhibitors as able to induce neutrophil apoptosis and reduce neutrophilic inflammation both in vitro and in vivo (Rahman et al. 2019). Here we expand on 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 to an inflammatory site in zebrafish larvae. Neratinib upregulates efferocytosis and reduces the number of dead neutrophils in mouse models of acute, but not chronic, lung injury, suggesting the drug may have therapeutic benefits in acute inflammatory settings. Phosphoproteomics analysis of human neutrophils shows that neratinib modifies the phosphorylation of proteins regulating apoptosis, migration and efferocytosis. This work identifies a potential efficacious mechanism for neratinib in acute lung inflammation by upregulating the clearance of dead neutrophils, and examination of the neutrophil phosphoproteome gives insight into the mechanisms by which this may be occurring.