Mechanosensory PNECs drive airway inflammation via secretoneurin-Slc23a2
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ABSTRACT:
PROVIDER: PRJNA1301907 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description:N6-methyladenosine (m6A) modification has been implicated in many cell processes and diseases. YTHDF1, a translation-facilitating m6A reader, is not previously shown to be related to allergic airway inflammation. Here, we report that YTHDF1 is highly expressed in allergic airway epithelial cells (AECs) and asthmatic patients, and influences proinflammatory responses. CLOCK, a subunit of the circadian clock pathway, is the direct target of YTHDF1. YTHDF1 augments CLOCK translation in an m6A-dependent manner. Allergens enhance the liquid‒liquid phase separation (LLPS) of YTHDF1 and drive the formation of a complex comprising dimeric YTHDF1 and CLOCK mRNA, which is distributed to stress granules (SGs). Moreover, YTHDF1 strongly activates NLRP3 inflammasome production and IL-1β secretion, leading to airway inflammatory responses, but these phenotypes are abolished by deleting CLOCK. These findings demonstrate that YTHDF1 is an important regulator of asthmatic airway inflammation, suggesting a potential therapeutic target for allergic airway inflammation.
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