X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc)

Bergmann C, Hallenberger L, Chenguiti Fakhouri S, Chenguiti Fakhouri S, Merlevede B, Brandt A, Dees C, Zhu H, Zehender A, Zhou X, Schwab A, Chen CW, Györfi AH, Matei AE, Chakraborty D, Trinh-Minh T, Rauber S, Coras R, Bozec A, Kreuter A, Ziemer M, Schett G, Distler J (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Article Number: annrheumdis-2020-219822

DOI: 10.1136/annrheumdis-2020-219822

Abstract

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). 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. 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. 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.

Authors with CRIS profile

Ludwig Hallenberger Professur für Molekulare Mechanismen der Organfibrose Sara Chenguiti Fakhouri Department of Medicine 3 – Rheumatology and Immunology Benita Merlevede Professur für Molekulare Mechanismen der Organfibrose Adrian Brandt Lehrstuhl für Arbeits-, Sozial- und Umweltmedizin Clara Dees Department of Medicine 3 – Rheumatology and Immunology Ariella Zehender Department of Medicine 3 – Rheumatology and Immunology Xiang Zhou Department of Medicine 3 – Rheumatology and Immunology Annemarie Schwab Interdisziplinäres Zentrum für Klinische Forschung IZKF Nachwuchsgruppe 1 Prof. Dr. Ceppi Andrea-Hermina Györfi Department of Medicine 3 – Rheumatology and Immunology Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Debomita Chakraborty Department of Medicine 3 – Rheumatology and Immunology Simon Rauber Department of Medicine 3 – Rheumatology and Immunology Roland Coras Institute of Neuropathology Aline Bozec Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

A079: The nuclear receptor TR4 regulates TGFbeta-induced fibroblast activation and tissue fibrosis Jan. 1, 2021 - June 30, 2023

Involved external institutions

Universitätsklinikum Leipzig DE Germany (DE) HELIOS Kliniken DE Germany (DE)

How to cite

APA:

Bergmann, C., Hallenberger, L., Chenguiti Fakhouri, S., Chenguiti Fakhouri, S., Merlevede, B., Brandt, A.,... Distler, J. (2021). X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc). Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2020-219822

MLA:

Bergmann, Christina, et al. "X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc)." Annals of the Rheumatic Diseases (2021).

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