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X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc)
  1. Christina Bergmann1,
  2. Ludwig Hallenberger1,
  3. Sara Chenguiti Fakhouri1,
  4. Benita Merlevede1,
  5. Amelie Brandt1,
  6. Clara Dees1,
  7. Honglin Zhu1,2,
  8. Ariella Zehender1,
  9. Xiang Zhou1,
  10. Annemarie Schwab3,
  11. Chih-Wei Chen1,
  12. Andrea Hermina Györfi1,
  13. Alexandru Emil Matei1,
  14. Debomita Chakraborty1,
  15. Thuong Trinh-Minh1,
  16. Simon Rauber1,
  17. Roland Coras4,
  18. Aline Bozec5,
  19. Alexander Kreuter6,
  20. Mirjana Ziemer7,
  21. Georg Schett1,
  22. Jörg H W Distler1
  1. 1 Department of Internal Medicine 3–Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
  2. 2 Department of Rheumatology and Immunology, Xiangya Hospital Central South University, Changsha, China
  3. 3 Interdisciplinary Centre for Clinical Research, University Hospital Erlangen, FAU-Erlangen-Nuremberg, Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
  4. 4 Department of Neuropathology, Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
  5. 5 Institute for Clinical Immunology University of Erlangen-Nuremberg, Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
  6. 6 Department of Dermatology and Allergology, HELIOS Sankt Elisabeth Klinik Oberhausen, Oberhausen, Nordrhein-Westfalen, Germany
  7. 7 Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig, Leipzig, Sachsen, Germany
  1. Correspondence to Dr Christina Bergmann, Department of Internal Medicine 3–Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Bayern, Germany; christina.bergmann{at}uk-erlangen.de

Abstract

Objective X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc).

Methods The expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice.

Results The expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-β) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/β-catenin signalling. Inactivation of XIAP reduces binding of β-catenin to TCF to in a TLE-dependent manner to block WNT/β-catenin-dependent transcription.

Conclusions Our data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-β/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/β-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.

  • scleroderma
  • systemic
  • pulmonary fibrosis
  • fibroblasts

Data availability statement

All data are available upon reasonable request from the corresponding author with the publication.

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Data availability statement

All data are available upon reasonable request from the corresponding author with the publication.

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Footnotes

  • Handling editor Josef S Smolen

  • LH and SCF contributed equally.

  • Contributors CB, LH and JHWD designed the study; CB, LH, SCF, BM, AB, CD, HZ, AZ, XZ, AS, C-WC, AHG, AEM, DC, TT-M, SR, RC, AB, AK and MZ acquired the data; CB, JHWD, LH, CD, GS and JHWD interpreted the data; CB; LH, SCF, BM, JHW and GS prepared the manuscript.

  • Funding Grants DI 1537/7–1, DI 1537/8–1, DI 1537/9–1 and −2, DI 1537/11–1, DI 1537/12–1, DI 1537/13–1, DI 1537/14–1, DI 1537/17–1, RA 2506/3–1, BE 7036/2–1 and ZH 809/1–1 of the German Research Foundation, SFB CRC1181 (project C01) and SFB TR221/project number 324 392 634 (B04) of the German Research Foundation, grants A64 and A79 of the IZKF in Erlangen, grant 2013.056.1 of the Wilhelm-Sander-Foundation, grants 2014_A47 and 2014_A184 of the Else-Kröner-Fresenius-Foundation, grant 14-12-17-1-Bergmann of the ELAN-Foundation Erlangen, Clinician Scientist Programme Erlangen (Advanced Module Christina Bergmann), Research award 2017 of the German Scleroderma Foundation (Deutsche Stiftung Sklerodermie) and a Career Support Award of Medicine of the Ernst Jung Foundation.

  • Competing interests JHWD has consultancy relationships and/or has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX and UCB; personal fees from Actelion, Anamar, ARXX, Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics and UCB, outside the submitted work, and is stock owner of 4D Science.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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