CCN1 drives asthmatic airway remodeling through amplification of TGF-β1/Smad3 signaling

TL;DR

The protein CCN1 worsens asthma by boosting TGF-β1 signaling, suggesting it could be a new target for treating airway damage.

Contribution

This study reveals a new feedback loop where CCN1 amplifies TGF-β1/Smad3 signaling to drive asthma-related airway remodeling.

Findings

CCN1 levels are elevated in asthmatic patients and linked to airway remodeling.

CCN1 knockdown reduces asthma symptoms and epithelial-mesenchymal transition in mice.

CCN1 enhances TGF-β1 signaling through a positive feedback loop involving Smad3 phosphorylation.

Abstract

Airway remodeling contributes significantly to chronic airflow limitation in asthma, but effective therapies are lacking. The matricellular protein CCN1 is implicated in fibrosis across multiple organ systems; however, its specific contribution to the pathogenesis of asthmatic airway remodeling has not been clearly delineated. This study was therefore designed to elucidate the functional role and regulatory mechanisms of CCN1 in this disease context.

To establish clinical relevance, we first compared CCN1 expression levels in bronchial biopsies and serum samples obtained from asthmatic patients versus those from healthy controls. To investigate its functional role in vivo, we utilized a murine model of ovalbumin (OVA)-induced chronic asthma, where the effects of CCN1 were interrogated using both shRNA-mediated knockdown and intranasal administration of recombinant protein. In parallel in vitro studies, we exposed human bronchial epithelial cells (BEAS-2B) to TGF-β1 and employed siRNA-mediated silencing or plasmid-driven overexpression to assess the impact of CCN1 on epithelial-mesenchymal transition (EMT) and cellular migration. The signaling mechanism was explored by analyzing Smad3 phosphorylation and its subcellular localization.

We observed a significant upregulation of CCN1 within both the airway mucosa and serum of asthmatic individuals, correlating with remodeling features. In the mouse model, CCN1 expression was similarly upregulated. Knockdown of CCN1 attenuated airway hyperresponsiveness, remodeling, and EMT, whereas exogenous CCN1 administration exacerbated these pathologies. In vitro, TGF-β1 was identified as a potent inducer of CCN1 expression in bronchial epithelial cells. Mechanistically, CCN1 was both necessary and sufficient for TGF-β1-driven EMT and pro-fibrotic responses. Notably, we unveiled a novel positive feedback loop initiated by TGF-β1-induced CCN1. This CCN1 induction, in turn, amplified canonical TGF-β1 signaling by promoting the phosphorylation and subsequent nuclear translocation of Smad3.

Our study identifies CCN1 as an important mediator of asthmatic airway remodeling. We demonstrate that CCN1 is induced by TGF-β1 and, in turn, enhances TGF-β1/Smad3 signaling, creating a positive feedback mechanism that promotes pro-fibrotic and EMT-like responses in bronchial epithelial cells. Collectively, these results highlight the CCN1 axis as a promising therapeutic target for mitigating airway remodeling in asthma.

The online version contains supplementary material available at 10.1186/s12931-026-03506-8.

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