TNFR2 overexpression ameliorates allergic airway inflammation and restores immune homeostasis associated with Hippo pathway modulation in an ovalbumin-induced allergic asthma mouse model

BACKGROUND: Asthma remains a major global health burden with limited therapeutic options. Tumor necrosis factor receptor 2 (TNFR2) has been implicated in immune regulation, yet its role and underlying mechanisms in asthma pathogenesis remain elusive. METHODS: An ovalbumin (OVA)-induced murine asthma model was established to investigate TNFR2 function. Recombinant adeno-associated virus serotype 9 vectors were administered three weeks prior to OVA sensitization to achieve prophylactic TNFR2 overexpression. Airway inflammation was assessed by histological staining and inflammation scoring. Bronchoalveolar lavage fluid was analyzed for inflammatory cell infiltration. Flow cytometry was employed to determine Th1/Th2 ratios in lymphoid tissues. Cytokine profiles were measured by ELISA. Western blotting and immunohistochemistry were conducted to evaluate Hippo signaling pathway activation. RESULTS: TNFR2 protein expression was significantly downregulated in asthmatic lung tissues. TNFR2 overexpression markedly attenuated airway inflammation, reduced mucus production, and decreased plasma IgE levels. The treatment restored Th1/Th2 immune balance and modulated cytokine production. Mechanistically, TNFR2 overexpression was associated with altered phosphorylation status of large tumor suppressor kinase (LATS) and yes-associated protein (YAP), suggesting potential involvement of the Hippo signaling pathway. CONCLUSIONS: These findings demonstrate that prophylactic TNFR2 overexpression ameliorates allergic airway inflammation via immunomodulation, with concomitant modulation of immune responses and Hippo pathway activity, identifying TNFR2 as a potential therapeutic target for asthma.