Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation
Neutrophilic inflammation with prolonged neutrophil survival is a hallmark of various inflammatory conditions, including chronic obstructive pulmonary disease (COPD). Despite the limited availability of specific therapies that can reverse neutrophilic inflammation, understanding the mechanisms regulating neutrophil survival could reveal new therapeutic targets. Screening 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbB kinases as common targets of compounds that accelerated inflammation resolution. In particular, ErbB inhibitors such as gefitinib, CP-724714, erbstatin, and tyrphostin AG825 significantly promoted apoptosis in human neutrophils, including those from COPD patients. Neutrophil apoptosis was also increased in zebrafish treated with Tyrphostin AG825 in vivo. Moreover, Tyrphostin AG825 reduced peritoneal inflammation in zymosan-treated mice, while increasing lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. In zebrafish, both Tyrphostin AG825 treatment and knockdown of egfra and erbb2 using CRISPR/Cas9 reduced inflammation. These findings demonstrate that ErbB kinase inhibitors have therapeutic potential for treating neutrophilic AG 825 inflammatory diseases.