Piezo1 channels orchestrate ILC2-dependent lung inflammation and development of airway hyperreactivity 9431

Abstract Description Immune cells rely on mechanosensitive ion channels such as Piezo1 to respond to physical stimuli, influencing their inflammatory response. We recently identified a significant role for Piezo1 channels on group 2 innate lymphoid cell (ILC2) metabolism, as Piezo1 engagement diminishes ILC2 mitochondrial function, reducing oxidative metabolism and bioenergetic activity. Consequently, activating Piezo1 channels in ILC2s reduces lung inflammation in multiple experimental ILC2-dependent airway hyperreactivity (AHR) models. Our new metabolome analysis reveals critical insights into the downstream mechanisms of Piezo1 channels, highlighting their significant impact on amino acid catabolism and fueling of the tricarboxylic acid (TCA) cycle. These metabolic effects are directly linked to the modulation of transcription factor activity, particularly members of the Kruppel-Like Factor (KLF) family, which are well-established regulators of immune cell function. Further investigation into Piezo1 channels in an established cohort of asthma patients at the University of Southern California demonstrated a direct correlation between Piezo1 expression in ILC2s and asthma severity. This suggests that Piezo1 channels play a pivotal role in immune cell regulation and asthma pathophysiology, as our findings further uncover a novel mechanism by which Piezo1 channels influence immune responses and provide a foundation for developing targeted therapies for asthma. Funding Sources National Institutes of Health grant: R01 HL144790, R01 HL151493, R01 AI145813, R01AI169687, R01 HL151769, and R01 HL 159804 (OA) Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)