Macrophages and the regulation of pulmonary fibrosis by Cadherin-11

Abstract

Abstract Pulmonary fibrosis is a chronic lung disease characterized by excessive deposition of extracellular matrix proteins by myofibroblasts leading to remodeling of the lung architecture. Alveolar macrophages play a key role in the development of pulmonary fibrosis and it has generally been associated with the polarization of these cells towards a profibrotic phenotype. Studies have shown the expression of the cell adhesion molecule Cadherin-11 (Cdh11) in alveolar macrophages from patients with pulmonary fibrosis and mice given bleomycin, and Cdh11-deficient mice are protected from bleomycin-induced pulmonary fibrosis suggesting an important role for Cdh11 in the pathogenesis of pulmonary fibrosis. In order to understand the role of Cdh11 in the development of pulmonary fibrosis, our study focuses on macrophages and aims to characterize the function and phenotype of Cdh11-deficient macrophages. We show that Cdh11-deficient mice have reduced numbers of tissue-resident alveolar macrophages compared to the wild type control mice and when given bleomycin, these mice have reduced numbers of CD11b+ monocyte-derived alveolar macrophages. Using BMDMs derived from Cdh11-deficient mice, we show that Cdh11-deficient macrophages have decreased expression of the alternative activation markers Arg1, Ym1, and CD206, and reduced secretion of TGF-β1, suggesting a reduced fibrotic phenotype. Furthermore, we show decreased phagocytosis, proliferation, and migration by Cdh11-deficient macrophages. These data suggest that Cdh11 may alter fibrotic responses by regulating the number and function of alveolar macrophages that are recruited to the lung.