Dupilumab Alleviates Pulmonary Fibrosis by Interrupting Profibrotic Macrophage-Fibroblast Crosstalk and IL4R/JAK/STAT Signaling

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) of unclear etiology. Dupilumab, a humanized monoclonal antibody binding to interleukin-4 receptor alpha (IL-4Rα), suppresses both IL-4 and IL-13 signaling pathways. However, the therapeutic potential in IPF is unclear. This research aimed to evaluate the antifibrotic efficacy of dupilumab and illustrate the underlying mechanisms. METHODS: The antifibrotic efficacy of dupilumab was assessed both in vitro and in vivo. In vitro, a fibroblast activation model and a macrophage-fibroblast co-culture model were established. In vivo, pulmonary fibrosis was induced in C57BL/6 mice by intratracheal bleomycin injection. Lung function, micro-computed tomography (micro-CT), histopathology, inflammatory responses, and fibrosis-related signaling pathways were assessed. RESULTS: Dupilumab significantly suppressed TGF-β1-induced fibroblast activation. In the macrophage-fibroblast coculture system, dupilumab inhibited the profibrotic phenotype of IL-4/IL-13-stimulated macrophages, as well as macrophage-induced myofibroblast activation. In bleomycin-challenged mice, dupilumab improved pulmonary function, alleviated radiographic and histopathological fibrosis, reduced inflammatory cell counts and inflammatory cytokine levels in bronchoalveolar lavage fluid. Mechanistically, dupilumab suppressed activation of both the TGF-β1/Smad and JAK/STAT pathways in fibrotic lung tissues. CONCLUSIONS: Dupilumab attenuates pulmonary fibrosis by disrupting profibrotic macrophage-fibroblast crosstalk and suppressing fibroblast activation. In preclinical models, dupilumab mitigated BLM-induced pulmonary inflammation and early-stage fibrosis in mice and inhibited the TGF-β1-Smad and JAK-STAT signal transduction cascades. These findings identify IL-4Rα-mediated signaling as a promising intervention point in pulmonary fibrosis and support further investigation of dupilumab as a candidate therapy for fibrotic lung diseases.