Non-cell-autonomous role of myofibroblasts in pulmonary fibrosis through lactate induction of M2 macrophage polarization

Abstract

Abstract Rationale There has been growing evidence that metabolic dysregulations play critical roles in the pathogenesis of lung fibrosis, particularly idiopathic pulmonary fibrosis (IPF). Recent studies from our group as well as others’ showed that lung myofibroblasts displayed augmented glycolysis and secreted more lactate than normal fibroblasts. In this study, we examined the effect of lactate, the end product of myofibroblast glycolysis, on the phenotypic alterations of macrophages that has been frequently implicated in lung fibrosis. Methods Levels of M2 macrophage markers were determined by real-time PCR and Western blotting. Lactate transportation into cells was inhibited by siRNA knockdown of lactate MCT1 or MCT1 inhibitors. Results First, we confirmed that alveolar macrophages (AM) from fibrotic mouse lungs exhibited a M2 macrophage phenotype, as evidenced by increased expression of M2 markers Arginase 1 (Arg1) and vascular endothelial growth factor (VEGF) in these cells. We found that lactate induced M2 polarization of bone marrow derived macrophages (BMDM) and AMs. Furthermore, conditional media from lung myofibroblasts as well as coculture with lung myofibroblasts promoted M2 differentiation of BMDMs and AMs. Lactate induced M2 polarization could be inhibited by incapacitating lactate transporter MCT1 through siRNA knockdown or specific inhibitors. Conclusions Our data suggest that lung myofibroblast derived lactate promotes the pro-fibrotic differentiation of lung macrophages. We provide novel insight into the mechanism by which lung myofibroblasts participate in the pathogenesis of lung fibrosis. Targeting lactate secretion or intake by lung macrophages could be novel strategies to treat lung fibrosis.