Tirzepatide improves neutrophilic inflammation in obese asthmatic mice by downregulating Th17 cell differentiation.

BACKGROUND: Asthma is a chronic respiratory disease affecting more than 330 million people worldwide. Obesity not only increases the risk of asthma attacks but also worsens symptoms and diminishes responsiveness to standard drug treatments. Tirzepatide, a dual GIP and GLP-1 receptor agonist, has demonstrated superior glycemic control and weight loss effects compared to selective GLP-1 receptor agonists in clinical trials. However, its impact on neutrophilic inflammation in obese asthmatic mice and the underlying molecular mechanisms remain unclear. METHODS: This study first established an obese mice model using a high-fat diet, followed by ovalbumin (OVA) sensitization and challenge to induce asthma. Glucose tolerance was assessed via oral glucose tolerance tests (OGTT), while body weight and blood glucose levels were monitored regularly. Pathological changes in lung tissue were evaluated using H&E and Masson’s trichrome staining. Serum leptin and insulin concentrations were measured by ELISA, and gene and protein expression levels were analyzed by qRT-PCR and Western blot, respectively. Additionally, the proportions of Th17 cells and neutrophils were determined by flow cytometry, and neutrophil migration was assessed through Transwell assays. RESULTS: Obesity exacerbates neutrophilic inflammation and asthma pathology in mice. Tirzepatide reduced airway inflammation and neutrophil aggregation in obese asthmatic mice by inhibiting the Notch signaling pathway, which in turn decreased the differentiation of Th17 cells. Both in vivo and in vitro experiments demonstrated that Tirzepatide suppresses the Notch signaling pathway, thereby reducing neutrophil recruitment mediated by Th17 cells. CONCLUSION: This study demonstrates that obesity-induced Th17 differentiation exacerbates neutrophilic inflammation in asthmatic mice. Tirzepatide reduces neutrophilic inflammation in obese asthmatic mice by inhibiting the NOTCH signaling pathway and suppressing Th17 differentiation. These findings offer new insights for the clinical treatment of obesity-related asthma.