Tezepelumab alters airway epithelial transcriptional responses and epithelial-smooth muscle signalling in uncontrolled asthma

Tezepelumab is a monoclonal antibody that targets thymic stromal lymphopoietin (TSLP). It reduces airway hyperresponsiveness, eosinophilia, mucus plugging, and asthma exacerbations, which are commonly caused by viral infections. Although clinical TSLP blockade attenuates virus-induced IL-33 and T2 cytokines in human bronchial epithelial cells (HBECs), the underlying mechanisms remain incompletely understood.

The aim of this study was to identify transcriptomic changes modulated by tezepelumab in HBECs and determine their downstream remodelling-related effects on bronchial smooth muscle cells (BSMCs).

HBECs from patients with uncontrolled asthma before and after 12 weeks of tezepelumab (n = 13) or placebo (n = 13) were expanded in vitro as submerged monocultures and subsequently exposed to poly(I:C). Transcriptomic profiling was performed, and selected targets were validated at mRNA and/or protein levels. Conditioned media from HBECs were applied to BSMCs to assess the expression of remodelling-associated mediators.

Tezepelumab treatment downregulated S100A8 and S100A9 expression in unstimulated HBECs. Following poly(I:C) stimulation, exploratory transcriptomic analysis identified enrichment of TNF-α/nuclear factor kappa B (NF-κB)-related pathways in placebo-treated HBECs compared with tezepelumab-treated HBECs. Validation analyses showed variable responses across the cohort, with attenuation observed primarily in patients with higher baseline inflammatory responses. In separate gain-of-function experiments, recombinant TSLP enhanced poly(I:C)-induced expression of S100A8, S100A9, TNFSF15, and TRAF1, together with increased NF-κB activation. Furthermore, conditioned media from poly(I:C)-stimulated HBECs collected after tezepelumab treatment induced lower TGF-β2 gene expression in BSMCs than conditioned media from placebo-treated HBECs.

Clinical TSLP blockade by tezepelumab was associated with altered epithelial transcriptional responses and reduced TGF-β2 gene expression in BSMCs exposed to epithelial conditioned media. These findings are hypothesis-generating and provide transcriptional insight into the mechanisms underlying the therapeutic benefits in asthma management.