Murine Airway Brush Cell Functions in Chronic Type II Inflammation

Abstract

Type-II (T2) inflammatory airway diseases are characterized by airway epithelial damage, epithelial remodeling, and goblet cell metaplasia, in addition to the immune cell influx. Brush cells (BrCs) are specialized chemosensory epithelial cells in the upper airway recently reported to generate interleukin-25 (IL-25) and cysteinyl leukotrienes (CysLTs) and to increase in number in murine models of T2 inflammation. In naive mice, Pou2f3 encodes the transcription factor POU Class 2 Homeobox 3 (POU2F3) and is required for BrC development and for regulating epithelial stemness, proliferation, and differentiation. However, the contribution of POU2F3 and BrCs to chronic allergic airway inflammation remains to be elucidated. Previous studies in the intestine demonstrated that chemosensory epithelial cells activated innate type 2 lymphoid cells (ILC2s) and promoted IL-13-dependent goblet cell metaplasia. Thus, we proposed that BrCs might elicit goblet cell metaplasia and inflammation in a model of chronic allergic lung inflammation. We repetitively challenged BrC-labeled ChAT-eGFP reporter mice, WT mice, and BrC-deficient Pou2f3-/- mice with a low-dose intranasal fungal aeroallergen, Alternaria alternata for four weeks to induce BrC expansion in both trachea and lungs. Strikingly, while BrC-deficient Pou2f3-/- mice had no significant difference in overall inflammation, increased lung Il13 and severe pulmonary goblet cell metaplasia, they had impaired goblet cell mucin release, demonstrating a novel paracrine function. These findings unveil the contribution of this enigmatic cell type in murine chronic T2 airway inflammation and an underappreciated function in eliciting goblet cell activation for mucus release.