Innate lymphoid cells promote airway epithelial repair through the amphiregulin-EGFR pathway (P3250)

Abstract Innate lymphoid cells (ILCs) are a recently described group of immune cells that regulate immunity and inflammation at barrier surfaces. While recent studies have implicated Group 2 ILCs as initiators of pathologic Type 2 airway inflammation, the tissue-protective roles of ILCs in the respiratory tract remain poorly understood. Using genome-wide transcriptional profiling, we identify that naïve lung-resident group 2 ILCs express multiple genes associated with tissue repair pathways, including the epidermal growth factor family member amphiregulin. Amphiregulin was increased in a model of influenza virus-induced lung injury and ILC depletion during infection resulted in decreased amphiregulin expression, reduced lung function and impaired airway remodeling. IL-33 promoted expression of amphiregulin in lung ILCs and administration of amphiregulin effectively restored airway tissue remodeling in ILC-depleted mice, suggesting that ILC-intrinsic amphiregulin is a central mediator of epithelial repair. Supporting this, chemical or genetic inhibition of the EGFR-amphiregulin pathway resulted in severely impaired lung function and a failure to restore airway tissue homeostasis, leading to increased host mortality. Taken together, these data indicate a critical role for group 2 ILCs in mediating lung tissue homeostasis though an IL-33-amphiregulin-EGFR axis and suggest that ILCs serve as a key link between the signaling pathways of Type 2 inflammation and tissue repair.