Dupilumab attenuate IL-4 and IL-13 synergistic effect on airway remodeling in asthma via blocking IL-4Rα/STAT6 axis

Airway fibrosis in severe asthma is a hallmark of disease pathology, yet the mechanisms driving fibroblast activation remain incompletely understood. While interleukin-4 (IL-4) and interleukin-13 (IL-13) are central to type 2 inflammation, their combined role in directly promoting human lung fibroblast-mediated fibrosis is not well defined. This study demonstrates that IL-4 and IL-13 act synergistically on asthmatic fibroblasts to potentiate a pro-fibrotic program via the shared interleukin-4 receptor alpha (IL-4Rα)/Signal Transducer and Activator of Transcription 6 (STAT6) axis. We found that diseased human lung fibroblasts (DHLFs) from asthmatic patients exhibited elevated expression of the type II receptor (IL-4Rα/IL-13Rα1) compared to normal human lung fibroblasts (NHLFs), priming them for activation. Consequently, combined IL-4/IL-13 stimulation synergistically enhanced STAT6 phosphorylation and robustly upregulated key extracellular matrix (ECM) components (collagen I/III, fibronectin) and regulators (matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1/2 (TIMP-1/2). Furthermore, IL-4 specifically emerged as the dominant driver of fibroblast proliferation. Critically, the IL-4Rα-blocking antibody dupilumab effectively abrogated this pro-fibrotic response. These findings provide a direct mechanistic basis for targeting the IL-4Rα pathway to mitigate airway remodeling and potentially alter the progressive course of fibrosis in patients with severe, type 2-high asthma.