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Al-Tamari, H.M.* ; Dabral, S.* ; Schmall, A.* ; Sarvari, P.* ; Ruppert, C.* ; Paik, J.* ; DePinho, R.A.* ; Grimminger, F.* ; Eickelberg, O. ; Guenther, A.* ; Seeger, W.* ; Savai, R.* ; Pullamsetti, S.S.*

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

EMBO Mol. Med. 10, 276-293 (2017)

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Published under the terms of the CC BY 4.0 license 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 (Foxo3 f.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.

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