GSDMB pyroptosis in NHBEs is driven independently of the inflammasome pathways and is regulated by IFNs in children with 17q21 asthma 3491

Abstract Description Recently, we have uncovered overexpression of gasdermin B (GSDMB), driven by rs7216389 SNP in the 17q21 locus, as driving gene of asthma pathophysiology. However, the direct impact of this genetic dysregulation on the airway mucosa remains poorly studied. Effect of overespression of GSDMB in normal human bronchial epithelial (NHBE) cells, stimulated with interferons (IFNγ, IFNα, IFNλ2) for the viral response, or inflammasome inducers (dsDNA, LPS + nigericin) for the bacterial response, was analyzed by qPCR, LDH assays, FLICA analysis, and alarmin ELISAs. Interferons upregulated GSDMB and CXCL10, but inflammasome activation did not induce GSDMB-dependent pyroptosis. GSDMB overexpression neither triggered spontaneous nor inflammasome-mediated pyroptosis, indicating reliance on IFN signaling and lytic cell death in viral, but not bacterial, infections. These findings suggest GSDMB dysregulation impairs interferon responses and cell lysis during viral infections in asthma, identifying it as a promising therapeutic target. Future research should explore GSDMB gene modulation and therapies targeting antiviral defense molecules, such as interferons, to restore mucosal immunity and alleviate asthma symptoms in children with the 17q21 risk allele. Funding Sources Supported by the German Center of Lung Research (DZL) funded by the Federal Ministry of Education and Research (BMBF), the Bavarian State Office for Health and Food Safety (LGL; K1-2497-GLB-20-V4) of the Bavarian State Ministry of Health and Care and by grants from Deutsche Forschungsgemeinschaft RTG2668 (Project A5, Project-ID: 435874434) to C.B. Schmidt-Weber. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)