Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease with high mortality and is refractory to treatment. Pulmonary macrophages can both promote and repress fibrosis, however molecular mechanisms regulating macrophage functions during fibrosis remain poorly understood. FOXM1 is a transcription factor and is not expressed in quiescent lungs. Herein, we show that FOXM1 is highly expressed in pulmonary macrophages within fibrotic lungs of IPF patients and mouse fibrotic lungs. Macrophage-specific deletion of Foxm1 in mice (my Foxm1 ^-/-) exacerbated pulmonary fibrosis. Inactivation of FOXM1 in vivo and in vitro increased p38 MAPK signaling in macrophages and decreased DUSP1, a negative regulator of p38 MAPK pathway. FOXM1 directly activated Dusp1 promoter. Overexpression of DUSP1 in FOXM1-deficient macrophages prevented activation of p38 MAPK pathway. Adoptive transfer of wild-type monocytes to my Foxm1 ^-/- mice alleviated bleomycin-induced fibrosis. Altogether, contrary to known pro-fibrotic activities in lung epithelium and fibroblasts, FOXM1 has anti-fibrotic function in macrophages by regulating p38 MAPK.

Author summary

Idiopathic pulmonary fibrosis (IPF) is a severe chronic lung disease, which is refractory to treatment. The environmental, age-related, and genetic factors increase susceptibility of the lung to injury. Repeated injury and deregulated repair result in scarring of the lung tissue and ultimate loss of respiratory function. Macrophages are involved at all stages of lung injury and repair, and can promote as well as repress fibrosis. However, molecular mechanisms regulating macrophage functions during fibrosis remain poorly understood. We have previously identified the FOXM1 protein to be highly increased in fibrotic lungs. High levels of FOXM1 in type II epithelial cells and fibroblasts exacerbated pulmonary fibrosis. In the present study, we found a novel and unexpected role of FOXM1. Contrary to pro-fibrotic functions of FOXM1 in epithelial cells and fibroblasts, FOXM1 has an anti-fibrotic role in macrophages. Mice lacking FOXM1 in macrophages developed severe pulmonary fibrosis following repeated lung injury with bleomycin. FOXM1 inhibited the p38 MAPK signaling pathway in pulmonary macrophages through transcriptional activation of DUSP1, a negative regulator of p38 MAPK pathway. Adoptive transfer of FOXM1-expressing monocytes protected FOXM1-deficient mice from bleomycin-induced pulmonary fibrosis. Altogether, FOXM1 has anti-fibrotic function in macrophages, limiting potential clinical use of FOXM1 inhibitors in IPF.