Tu103 - Piezo1 Channels Constrain ILC2 Bioenergetic and Effector Functions and Ameliorate Airway Hyperreactivity

Stephen Shen – University of Southern California; Xin Li – University of Southern California; Yoshihiro Sakano – University of Southern California; Mohammad Kazemi – University of Southern California; Kei Sakano – University of Southern California; Omid Akbari – University of Southern California

Abstract Text: Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here we report that Piezo1 channels repress group 2 innate lymphoid cell (ILC2)-driven type 2 inflammation in the lungs. Piezo1 channels are induced on lung ILC2s upon activation both ex vivo and in vivo, with their expression inversely correlated with known ILC2 activation markers at the single cell transcriptomic and protein levels. Conversely, we found that genetic ablation of Piezo1 specifically in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). As a result, in vivo administration of Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation in multiple experimental models of ILC2-dependent AHR, with a notable effect on lung ILC2 effector functions. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation through a specific mechanistic process involving the modulation of transcription factor expression and activation within ILC2s. Our observations further suggest a major role for Piezo1 channels on ILC2 metabolism as Piezo1 engagement notably reduces ILC2 mitochondrial function, resulting in a reduction of oxidative metabolism and bioenergetic activity. Human circulating ILC2s express and induce Piezo1 upon activation, with Piezo1 engagement able to limit human ILC2 cytokine production, proliferation and bioenergetic activities. Conversely, in vivo administration of Yoda1 to humanized mice reduces human ILC2-driven AHR and lung inflammation. Our studies define Piezo1 as a critical regulator of ILC2s and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.