FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis

Hamza M. Al-Tamari, Swati Dabral, Anja Schmall, Pouya Sarvari, Clemens Ruppert, Jihye Paik, Ronald A. DePinho, Friedrich Grimminger, Oliver Eickelberg, Andreas Guenther, Werner Seeger, Rajkumar Savai, Soni S. Pullamsetti

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-β1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3−/−) or fibroblast-specific (Foxo3f.b −/−) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN-01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype in vitro and blocked the bleomycin-induced lung fibrosis in vivo. These studies implicate FoxO3 as a critical integrator of pro-fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.

Original languageEnglish (US)
Pages (from-to)276-293
Number of pages18
JournalEMBO Molecular Medicine
Volume10
Issue number2
DOIs
StatePublished - Feb 2018

Keywords

  • fibroblast
  • forkhead box O transcription factors
  • idiopathic pulmonary fibrosis
  • myofibroblast
  • transdifferentiation

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint

Dive into the research topics of 'FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis'. Together they form a unique fingerprint.

Cite this