Non-neuronal cells, including epithelial cells, can produce acetylcholine (ACh). Muscarinic ACh receptor antagonists are used clinically to treat asthma and other medical conditions; however, knowledge regarding the roles of ACh in type 2 immunity is limited. To investigate the roles of epithelial ACh in allergic immune responses. Human bronchial epithelial (HBE) cells were cultured with allergen extracts, and their ACh production and interleukin (IL)-33 secretion were studied in vitro. To investigate immune responses in vivo, naïve BALB/c mice were treated intranasally with different muscarinic ACh receptor antagonists and then exposed intranasally to allergens. At steady state, HBE cells expressed cellular components necessary for ACh production, including choline acetyltransferase and organic cation transporters. Exposure to allergens caused HBE cells to rapidly release ACh into the extracellular medium. Pharmacologic or siRNA-based blocking of ACh production or autocrine action through the M3 muscarinic ACh receptors (M3R) in HBE cells suppressed allergen-induced ATP release, calcium mobilization, and extracellular secretion of IL-33. When naïve mice were exposed to allergens, ACh was quickly released into the airway lumen. A series of clinical M3R antagonists inhibited allergen-induced IL-33 secretion and innate type 2 immune response in the mouse airways. In a preclinical murine model of asthma, an ACh receptor antagonist suppressed allergen-induced airway inflammation and airway hyperreactivity. ACh is released quickly by airway epithelial cells upon allergen exposure and plays an important role in type 2 immunity. The epithelial ACh system can be considered a therapeutic target in allergic airway diseases.

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