Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis

J Biol Chem. 2017 Jun 23;292(25):10490-10519. doi: 10.1074/jbc.M116.752469. Epub 2017 Apr 7.


Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGFβ1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 (NOX4) enzyme, which catalyzes the reduction of O2 to hydrogen peroxide (H2O2), has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates NOX4 to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-β-1-induced CD44V6 regulates the NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation. Specifically, we found that NOX4/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with TGFβ1/TGFβRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both NOX4 and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic (CD44v6 shRNA) or a small molecule inhibitor (CD44v6 peptide) targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.

Keywords: CD44; NOx; differentiation; hyaluronan; reactive oxygen species (ROS).

MeSH terms

  • Animals
  • Autocrine Communication*
  • Cell Differentiation / genetics
  • Disease Models, Animal
  • Female
  • Humans
  • Hyaluronan Receptors / biosynthesis*
  • Hyaluronan Receptors / genetics
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Male
  • Mice
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*


  • CD44v6 antigen
  • Hyaluronan Receptors
  • Reactive Oxygen Species
  • Receptors, Transforming Growth Factor beta
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Transcription Factor AP-1
  • Transforming Growth Factor beta1
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human
  • Nox4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I