TSLP Mediated Regulation of Airway Inflammation: Associations of Genetic Polymorphisms with Clinical Heterogeneity in Respiratory Diseases

Abstract

Airway epithelial cells are key regulators of immune responses in respiratory disease through the release of alarmin cytokines, including thymic stromal lymphopoietin (TSLP). As an upstream mediator of type 2 inflammation, TSLP is elevated in asthma and inducible during viral respiratory infections. Genetic variation within the TSLP locus has been associated with asthma susceptibility; however, how these variants influence epithelial inflammatory responses across disease contexts remains unclear. This thesis investigated whether TSLP polymorphisms are associated with variation in airway epithelial inflammation during viral infection, asthma severity, and allergen-induced responses. Associations between TSLP genetic variants (rs2289276, rs3806933, rs1837253) and systemic inflammation were first examined in SARS-CoV-2 infection. Genotype frequencies did not differ by infection status or disease severity. However, minor alleles of rs2289276 and rs3806933 were associated with lower circulating TSLP levels, suggesting a modulatory role in epithelial responses to viral infection, although not a major determinant of COVID-19 severity. In asthma cohorts, rs2289276 and rs3806933 were associated with reduced odds of asthma. rs2289276 carriers were more likely to have mild rather than moderate–severe disease and exhibited lower long-form TSLP expression and reduced sputum TSLP protein levels, alongside decreased eosinophilic inflammation. Sex-stratified analyses revealed lower TSLP levels in female carriers. In an allergen challenge model, variant carriers demonstrated attenuated inflammatory responses, including reduced IL-5, IL-4, and eosinophilia, as well as improved lung function recovery. RNA sequencing further showed that rs3806933 was associated with reduced expression of genes involved in epithelial–immune signaling and cytokine pathways following allergen exposure. Collectively, these findings demonstrate that TSLP polymorphisms are associated with context-dependent variation in airway inflammation, linking genetic regulation of epithelial responses to molecular, cellular, and physiologic features of asthma.