Piezo1-mediated Mechanotransduction Shapes ILC2 Translational Activity, Functions, and Lung Pathogenicity [II]

Group-2 innate-lymphoid cells (ILC2s) are critical mediators of the type-2 immune responses in multiple lung pathologies. We show that Piezo1, a mechanosensitive ion channel, plays a key role in regulating ILC2 functions by linking mechanical cues to biochemical signaling pathways. Both murine and human ILC2s strongly express Piezo1, and its activation by Yoda1 selectively enhances IL-13 production through calcium influx, which activates the mTOR-S6K pathway. This pathway leads to translational reprogramming, favoring IL-13 translation. Piezo1-deficient in ILC2s impairs this process, reducing IL-13 levels and resulting in attenuated lung inflammation and fibrosis in mouse models of IL-33- or Alternaria alternata-induced airway inflammation and bleomycin-induced fibrosis. These findings position Piezo1 as a critical mediator of ILC2-driven type-2 immune responses and highlight its potential as a therapeutic target for lung diseases characterized by excessive inflammation. This streamlined understanding of Piezo1 function improves focus on its mechanistic role in lung pathology. Overall design: Mouse lung ILCs sample from tamoxifen inducible Piezo1fl/fl x Id2-CreERT2 (cKO) or llittermate control Piezo1fl/fl mice (WT). We injected tamoxifen for Cre recombinase induction and intratracheal injection of rmIL-33 (250ng/ml) for 3 days interval for ILC2s enrichment. After last days of rmIL-33 injection, we sorted CD45+ Lin- CD127+ ILCs by Aria FACS sorter (BD bioscience).