MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

Aran Singanayagam; Joseph Footitt; Benjamin T Kasdorf; Matthias Marczynski; Michael T Cross; Lydia J Finney; Maria-Belen Trujillo Torralbo; Maria Calderazzo; Jie Zhu; Julia Aniscenko; Thomas B Clarke; Philip L Molyneaux; Nathan W Bartlett; Miriam F Moffatt; William O Cookson; Jadwiga Wedzicha; Christopher M Evans; Oliver Lieleg; Patrick Mallia; Sebastian L Johnston

In addition to our observation that MUC5AC directly augments rhinovirus-induced airway inflammation, a number of previous studies have also demonstrated that inflammatory mediators such as neutrophil elastase and IL-1b can directly induce MUC5AC expression in lung epithelium 35 . We therefore speculate that mucin-induced airway inflammation might trigger further production of MUC5AC leading to a vicious cycle which contributes to enhanced airway inflammation and mucus hypersecretion to drive exacerbation severity in COPD. We thus hypothesised that early targeting of MUC5AC during rhinovirus infection might beneficially interrupt this cycle and evaluated the effect of upstream inhibition of rhinovirus-induction of MUC5AC using the EGFR inhibitor AG1478 in a COPD exacerbation mouse model. AG1478 suppressed rhinovirus-induced MUC5AC levels, accompanied by reduced airway inflammation, pro-inflammatory cytokines and chemokines, neutrophil elastase and AHR, as well as enhanced SLPI production and reduced bacterial loads in rhinovirus-infected elastase-treated mice. Importantly, AG1478 had no impact on anti-viral responses, or virus control, reassuringly indicating that therapies aimed at inhibiting MUC5AC production would not be expected to adversely affect anti-viral host-defence. Jing et al recently reported in COPD airway epithelial cell cultures that administration of an EGFR inhibitor had no effect on RV-induction of MUC5AC and concluded that EGFR does not play a role in promoting virus-induced mucin expression in COPD 36 . However, in this study, the authors examined mucin expression solely at a late timepoint (15 days) post RV infection and did not evaluate effects of the treatment on mucin expression at earlier timepoints nor subsequent effects on production of inflammatory mediators. The data from our human challenge model indicates that peak RV induction of MUC5AC occurs at a much earlier timepoint (3 days) and previous studies have shown that EGFR inhibition can attenuate the early induction of MUC5AC in RV-stimulated airway epithelial cell cultures 23, 37 Our data in a mouse model of COPD-like disease supports the assertion that the early production of MUC5AC in response to RV infection occurs through EGFR and is thus amenable to therapeutic inhibition. A previous study using an inhaled EGFR inhibitor in stable COPD reported more effective EGFR inhibition was related to greater decreases in epithelial mucin stores at higher doses, but this drug was poorly tolerated 38 . Systemic EGFR antagonists are now commonly used in lung adenocarcinoma therapy 39 . Our data in mice now provides justification for human studies to evaluate the role of repurposing these agents for use in COPD exacerbations to inhibit MUC5AC production which could theoretically suppress airway inflammation, reduce secondary bacterial infection and diminish exacerbation severity.