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Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis
Shibnath Ghatak1, Vincent C Hascall2, Roger R Markwald3
1From the Department of Regenerative Medicine and Cell Biology, ghatak@musc.edu.
Abstract:
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.
Insights
Idiopathic pulmonary fibrosis (IPF) involves CD44 variant 6 (CD44v6) and NADPH oxidase 4 (NOX4) signaling. Targeting CD44v6 may offer new therapies for lung fibrosis by disrupting this pathway.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Molecular Biology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited treatment options.
- Fibroblast to myofibroblast differentiation is central to IPF pathogenesis.
- The roles of CD44 variant 6 (CD44v6) and NADPH oxidase 4 (NOX4) in IPF are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which TGF-β1-induced CD44v6 regulates NOX4/ROS signaling in myofibroblast differentiation.
- To investigate the positive-feedback loop involving CD44v6 and TGFβ1 signaling in fibrogenesis.
- To evaluate the therapeutic potential of targeting CD44v6 in lung fibrosis models.
Main Methods:
- Investigated the regulation of NOX4/ROS signaling by CD44v6 in lung fibroblasts.
- Analyzed the interplay between CD44v6, TGFβ1, and AP-1 activity.
- Utilized genetic (shRNA) and pharmacological (peptide inhibitor) approaches to target CD44v6 in murine lung injury models.
Main Results:
- CD44v6 positively regulates NOX4/ROS signaling, which is crucial for myofibroblast differentiation.
- A positive-feedback loop exists between CD44v6 and TGFβ1 signaling, enhancing NOX4/ROS production.
- Targeting CD44v6 abrogated fibrogenesis in experimental lung injury models.
- Both NOX4 and CD44v6 were upregulated in injured mouse lungs and human IPF.
Conclusions:
- CD44v6 plays a critical role in mediating myofibroblast differentiation and fibrogenesis through the NOX4/ROS pathway.
- The CD44v6/TGFβ1 signaling axis represents a potential therapeutic target for IPF and other fibrotic lung diseases.