Beyond-Classical β2-adrenergic receptor signaling in human airway smooth muscle: A role for EZH2

β2-agonists are typically used to treat asthma. However prolonged use of these β2-agonists results in desensitization of the β2-adrenergic receptor (β2AR), a process significantly influenced by the inflammatory milieu, especially cytokines such as IL4 and IL13. The β2AR is also targeted by transcriptional repressor EZH2. This protein is dysregulated in many cancers and could therefore also be improperly affecting β2AR function in asthma. Here we show that T2 cytokines upregulate EZH2 expression which attenuates β2AR function. Further, we observe that the activation of the bitter taste receptor family (TAS2R), which has been shown to cause relaxation under conditions that desensitize β2AR, decreases EZH2 expression and improves airway obstruction. Thus, T2 cytokine-mediated EZH2 upregulation could lead to β2AR desensitization, indicating EZH2 to be a potential therapeutic target for asthma treatment.