Article Text

PDF
Extended report
Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis
  1. Katrin Palumbo-Zerr1,
  2. Alina Soare1,2,
  3. Pawel Zerr1,
  4. Andrea Liebl1,
  5. Rossella Mancuso1,
  6. Michal Tomcik1,3,
  7. Barbora Sumova1,3,
  8. Clara Dees1,
  9. Chih-Wei Chen1,
  10. Thomas Wohlfahrt1,
  11. Tatjana Mallano1,
  12. Alfiya Distler1,
  13. Andreas Ramming1,
  14. Kolja Gelse4,
  15. Carina Mihai2,
  16. Oliver Distler5,
  17. Georg Schett1,
  18. Jörg H W Distler1
  1. 1Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Internal Medicine and Rheumatology, Dr. I. Cantacuzino Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
  3. 3Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
  4. 4Department of Trauma Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
  5. 5Research of Systemic Autoimmune Diseases, Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc).

Methods The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)β receptor I.

Result The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGFβ/SMAD3-dependent manner. TWIST1 in turn enhanced TGFβ-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGFβ promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1.

Conclusions Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGFβ signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGFβ signalling in SSc.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

Statistics from Altmetric.com

Footnotes

  • Handling editor Tore K Kvien

  • Contributors KP-Z and JHWD designed the research: KP-Z, AS, PZ, AL, RM, MT, BS, CD, C-WC, TW, TM, AD, AR performed the research; KP-Z, AS, PZ, AL, AR, KG, CM, OD, GS, JWHD analyzed the data; KP-Z, AS and JWDH wrote the manuscript.

  • Funding This study was supported by grants DI 1537/4-1, DI 1537/5-1, DI 1537/7-1, DI 1537/8-1, DI 1537/9-1 of the German Research Association (DFG), grants A57 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 and the project 00023728 from the Ministry of Health of the Czech Republic for conceptual development and SVV260031. AS received a scientific training bursary from the European League Against Rheumatism (2014) and was holding an Articulum Fellowship (2015).

  • Competing interests OD has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, Medac, Biovitrium, Boehringer Ingelheim, Novartis, 4D Science, Active Biotech, Bayer, Sinoxa, Serodapharm, EpiPharm, GSK, Pharmacyclics and Biogen. JHW D has consultancy relationships and/or has received research funding from Actelion, Active Biotech, Array Biopharma, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, JB Therapeutics, Novartis, Sanofi-Aventis, Sigma Tau and UCB in the area of potential treatments of SSc and is stock owner of 4D Science GmbH.

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

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.