Sphingosine kinase 1/s1p signaling contributes to pulmonary fibrosis by activating hippo/yap pathway and mitochondrial reactive oxygen species in lung fibroblasts

Long Shuang Huang, Tara Sudhadevi, Panfeng Fu, Prasanth Kumar Punathil-Kannan, David Lenin Ebenezer, Ramaswamy Ramchandran, Vijay Putherickal, Paul Cheresh, Guofei Zhou, Alison W. Ha, Anantha Harijith, David W. Kamp, Viswanathan Natarajan*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β-or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β-or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis.

Original languageEnglish (US)
Article number2064
JournalInternational journal of molecular sciences
Volume21
Issue number6
DOIs
StatePublished - Mar 2 2020

Keywords

  • BLM
  • Lung fibroblast
  • Pulmonary fibrosis
  • S1P
  • SPHK1
  • TGF-β
  • YAP signaling

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Huang, L. S., Sudhadevi, T., Fu, P., Punathil-Kannan, P. K., Ebenezer, D. L., Ramchandran, R., Putherickal, V., Cheresh, P., Zhou, G., Ha, A. W., Harijith, A., Kamp, D. W., & Natarajan, V. (2020). Sphingosine kinase 1/s1p signaling contributes to pulmonary fibrosis by activating hippo/yap pathway and mitochondrial reactive oxygen species in lung fibroblasts. International journal of molecular sciences, 21(6), [2064]. https://doi.org/10.3390/ijms21062064