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The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis
  1. Gerhard Krönke1,2,
  2. Nicole Reich1,
  3. Carina Scholtysek1,2,
  4. Alfiya Akhmetshina1,
  5. Stefan Uderhardt1,2,
  6. Pawel Zerr1,
  7. Katrin Palumbo1,
  8. Veronika Lang1,
  9. Clara Dees1,
  10. Oliver Distler3,
  11. Georg Schett1,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Jörg H W Distler, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Background Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc.

Objectives To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis.

Methods Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO−/− mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO−/− mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms

Results In both models, 12/15-LO−/− mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO−/− fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects.

Conclusions These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.

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Footnotes

  • GK and NR contributed equally to the manuscript.

  • Funding Grants DI 1537/1-1, DI 1537/2-1, DI 1537/4-1, AK 144/1-1 and SCHE 1583/7-1 of the Deutsche Forschungsgesellschaft, grants A20 and A40 of the IZKF in Erlangen, the ELAN-Program of the University of Erlangen-Nuremberg and the Career Support Award of Medicine of the Ernst Jung Foundation

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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