Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway
Autoři:
Chinmayee Goda aff001; David Balli aff001; Markaisa Black aff001; David Milewski aff001; Tien Le aff001; Vladimir Ustiyan aff001; Xiaomeng Ren aff001; Vladimir V. Kalinichenko aff001; Tanya V. Kalin aff001
Působiště autorů:
Division of Pulmonary Biology, the Perinatal Institute of Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, United States of America
aff001; Center for Lung Regenerative Medicine, the Perinatal Institute of Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, United States of America
aff002
Vyšlo v časopise:
Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008692
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008692
Souhrn
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 (myFoxm1-/-) 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 myFoxm1-/- 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.
Klíčová slova:
Alveolar macrophages – Collagens – Fibroblasts – Fibrosis – Macrophages – MAPK signaling cascades – Mouse models – Pulmonary fibrosis
Zdroje
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