Cadherin-26 contributes to an M2-like macrophage polarization and TGF-β1 expression via the CTNNB1-STAT3 axis in interstitial lung disease.

Abstract

Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by inflammation and interstitial fibrosis of the pulmonary parenchyma. Alternative activation of macrophages can promote fibrosis through the secretion of TGF-β1 in ILD. However, the mechanisms regulating alternative macrophage activation and TGF-β1 expression in ILD patients remain unclear. We demonstrated that cadherin-26 (CDH26) expression is upregulated in ILD patients' lungs and inversely correlated with lung function. CDH26 is predominantly expressed in macrophages in bronchoalveolar lavage cells from ILD patients. In a mouse model of bleomycin-induced pulmonary fibrosis, we found that macrophage-specific Cdh26 deficiency significantly attenuated bleomycin-induced fibrosis, collagen deposition, alternative activation-associated (M2-like) macrophage polarization, and Tgf-β1 expression. In vivo and vitro experiments showed that Cdh26 deficiency was associated with suppression of the Ctnnb1-Stat3 signaling axis in macrophages. Our study delineates a novel CDH26-mediated signaling in lung fibrosis, and CDH26 may represent a potential therapeutic target for ILD.