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. 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).