G-CSF drives pathophysiology of RV-induced allergic asthma exacerbations by potentiating neutrophilic inflammation and ILC2 function

Background Rhinovirus (RV)-induced allergic asthma exacerbations are an important unmet clinical need. Such episodes are characterised by augmented neutrophilic and type 2 inflammation, however mechanistic links between viral infection and ensuing pathophysiology are poorly understood. Granulocyte-colony stimulating factor (G-CSF) is classically recognized as a regulator of neutrophilic inflammation, but we have shown that it can also potentiate type 2 innate lymphoid cell (ILC2) function. Thus, we hypothesised that RV-induced G-CSF drives pathology of asthma exacerbations through concomitantly augmenting neutrophilic and ILC2 responses. Methods Healthy controls and asthmatic patients were experimentally inoculated with RV16. Bronchoalveolar lavage and bronchial brushings were collected at baseline and after infection. Subsequently, G-CSF was neutralised in an ovalbumin (OVA)-RV mouse model of asthma exacerbation to assess its capacity to ameliorate pathology. Results: RV16 infection of asthmatic patients resulted in a significant induction of G-CSF protein and transcript, which correlated with levels of neutrophilia, type 2 inflammation and adverse clinical outcomes. These findings were directly recapitulated in the murine OVA-RV model, whereby subsequent G-CSF neutralisation reduced neutrophilic and ILC2 responses. Conclusions G-CSF acts as an instigator of pathophysiology in the context of viral exacerbations of allergic asthma, owing to its capacity to potentiate both neutrophilic and type 2 inflammation. Antibodies targeting G-CSF receptor have completed phase I trials and could represent a new therapeutic strategy for asthma exacerbations.