Mechanosensory PNECs drive airway inflammation via secretoneurin-Slc23a2

The respiratory epithelium is the body’s most exposed internal surface to airborne antigens and pathogens. Beyond serving as a physical barrier, epithelial cells actively work to expel threats by secreting mucus and cough-mediated pressure dynamics and orchestrating an immune response1. However, the mechanisms by which epithelial cells transduce mechanical changes in the airway during allergic immune activation remain unclear. We demonstrated that pulmonary endocrine cells (PNECs), a specialized rare cell population, sense airway pressure fluctuations via the mechanosensitive ion channel Piezo2 and promote eosinophilic inflammation by secreting secretoneurin, a chromogranin family neuropeptide. Piezo2-expressing PNECs form clusters at bronchial bifurcation sites, and their anatomical locations tend to experience maximal mechanical stress2. PNECs actively secrete secretoneurin in response to positive pressure ventilation in vivo. Intratracheal administration of secretoneurin induces massive infiltration of eosinophils and eosinophil extracellular trap cell death (EETosis), a pathological process central to airway inflammation3. In a murine model of Aspergillus-induced severe asthma, conditional deletion of Piezo2 or secretoneurin-encoding Scg2 specifically in PNECs, significantly ameliorated eosinophilic inflammation in the lungs. Unbiased proteoliposome screening identified sodium-dependent ascorbate transporter SLC23A2 as a binding partner of secretoneurin in eosinophils. In human respiratory tissues, a spatial transcriptome analysis and immunohistochemistry confirmed the expression of both PIEZO2 and SCG2 in PNECs. Furthermore, patients with lung eosinophilic inflammation showed significantly higher secretoneurin concentrations in bronchoalveolar lavage fluid than other patients. These results revealed a previously unrecognized epithelial mechanosensory pathway that drives eosinophilic inflammation via the PIEZO2-secretoneurin-SLC23A2-EETosis axis, thereby providing potential therapeutic targets for eosinophilic airway diseases. We characterized the cytological characteristics of pulmonary neuroendocrine cells using scRNAseq of mouse lungs and Xenium spatial transcriptomics of human lung tissue, and elucidated the secretion mechanism of secretoneurin induced by pressure stimulation, as well as the function of secretoneurin and the identification of its receptors in vivo and in vitro using mouse eosinophils and human sample analysis.