The role of X-linked inhibitor of apoptosis protein (XIAP) in Systemic Sclerosis and other fibrosing disorders
Final Report Abstract
Systemic sclerosis (SSc) is a chronic fibrosing disease with the highest disease-specific morbidity and mortality among rheumatic diseases. The mechanisms of fibrosis development and maintenance are only partially understood. X-linked Inhibitor of Apoptosis Protein (XIAP) is a protein of the Inhibitor of Apoptosis Protein (IAP) family and had not been studied in the context of fibrosing diseases before the start of this project. IAP proteins are ubiquitously expressed proteins with diverse cellular functions. In the funded project, we demonstrated that XIAP is expressed at higher levels in fibrotic tissue from biospies of affected skin of SSc patients compared to skin samples from controls. Similar observations were described in fibrotic tissue from murine fibrosis models (bleomycin-induced skin fibrosis, model of scleroderma-like graft-versus-host disease, topoisomerase I-induced skin fibrosis). We showed that inhibition of XIAP leads to reduced activation of fibroblasts and differentiation into myofibroblasts in vitro. Additionally, we demonstrated that Xiap inhibition results in reduced skin and lung fibrosis in several murine fibrosis models: bleomycin-induced skin fibrosis, skin fibrosis in Wnt10b transgenic mice, and topoisomerase I-mediated skin and lung fibrosis. The expression of XIAP is induced by TGF-β in a SMAD-dependent manner. We demonstrated that XIAP is an important link between two profibrotic signaling pathways, TGF-β- and WNT/β-catenin mediated signaling: XIAP interacts with the WNT transcriptional repressor TLE3, which leads to decreased binding of β-catenin to the transcription factor complex TCF/LEF, thereby inhibiting the activation of WNT target genes. Inhibition of XIAP enhances TLE3 binding to TCF/LEF and suppresses the activation of WNT target genes. These findings could serve as a basis for further characterization of XIAP as a target for antifibrotic therapies in SSc and other fibrosing diseases.
Publications
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Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation. Journal of Experimental Medicine, 218(9).
Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Fuchs, Maximilian; Liang, Chunguang; Rigau, Aleix Rius; Hong, Xuezhi; Zhu, Honglin; Luber, Markus; Bergmann, Christina; Dees, Clara; Ludolph, Ingo; Horch, Raymund E.; Distler, Oliver; Wang, Jiucun; Bengsch, Bertram; Schett, Georg; Kunz, Meik & Distler, Jörg H.W.
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X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc). Annals of the Rheumatic Diseases, 80(8), 1048-1056.
Bergmann, Christina; Hallenberger, Ludwig; Chenguiti Fakhouri, Sara; Merlevede, Benita; Brandt, Amelie; Dees, Clara; Zhu, Honglin; Zehender, Ariella; Zhou, Xiang; Schwab, Annemarie; Chen, Chih-Wei; Györfi, Andrea Hermina; Matei, Alexandru Emil; Chakraborty, Debomita; Trinh-Minh, Thuong; Rauber, Simon; Coras, Roland; Bozec, Aline; Kreuter, Alexander ... & Distler, Jörg H. W.
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Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT. European Journal of Nuclear Medicine and Molecular Imaging, 50(6), 1629-1635.
Treutlein, Christoph; Distler, Jörg H. W.; Tascilar, Koray; Fakhouri, Sara Chenguiti; Györfi, Andrea-Hermina; Atzinger, Armin; Matei, Alexandru-Emil; Dees, Clara; Büttner-Herold, Maike; Kuwert, Torsten; Prante, Olaf; Bäuerle, Tobias; Uder, Michael; Schett, Georg; Schmidkonz, Christian & Bergmann, Christina
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Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Annals of the Rheumatic Diseases, 82(8), 1117-1120.
Bergmann, Christina; Müller, Fabian; Distler, Jörg H. W.; Györfi, Andrea-Hermina; Völkl, Simon; Aigner, Michael; Kretschmann, Sascha; Reimann, Hannah; Harrer, Thomas; Bayerl, Nadine; Boeltz, Sebastian; Wirsching, Andreas; Taubmann, Jule; Rösler, Wolf; Spriewald, Bernd; Wacker, Jochen; Atzinger, Armin; Uder, Michael; Kuwert, Torsten ... & Schett, Georg
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Mutual Amplification of GLI2/Hedgehog and Transcription Factor JUN/AP‐1 Signaling in Fibroblasts in Systemic Sclerosis: Potential Implications for Combined Therapies. Arthritis & Rheumatology, 77(1), 92-98.
Bergmann, Christina; Chenguiti Fakhouri, Sara; Trinh‐Minh, Thuong; Filla, Tim; Rius Rigau, Aleix; Ekici, Arif B.; Merlevede, Benita; Hallenberger, Ludwig; Zhu, Honglin; Dees, Clara; Matei, Alexandru‐Emil; Auth, Janina; Györfi, Andrea‐Hermina; Zhou, Xiang; Rauber, Simon; Bozec, Aline; Dickel, Nicholas; Liang, Chunguang; Kunz, Meik ... & Distler, Jörg H.W.
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CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series. The Lancet Rheumatology, 7(2), e83-e93.
Auth, Janina; Müller, Fabian; Völkl, Simon; Bayerl, Nadine; Distler, Jörg H. W.; Tur, Carlo; Raimondo, Maria G.; Chenguiti Fakhouri, Sara; Atzinger, Armin; Coppers, Birte; Eckstein, Markus; Liphardt, Anna-Maria; Bäuerle, Tobias; Tascilar, Koray; Aigner, Michael; Kretschmann, Sascha; Wirsching, Andreas; Taubmann, Jule; Hagen, Melanie ... & Bergmann, Christina
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Disturbed Spatial WNT Activation—A Potential Driver of the Reticularized Skin Phenotype in Systemic Sclerosis. Arthritis & Rheumatology, 77(6), 740-749.
Fakhouri, Sara Chenguiti; Zhu, Honglin; Li, Yi‐Nan; Ronicke, Moritz; Rigau, Aleix Rius; Dees, Clara; Konstantinidis, Laura; Schmid, Ralf; Matei, Alexandru‐Emil; Eckstein, Markus; Geppert, Carol; Ludolph, Ingo; Kreuter, Alexander; Sticherling, Michael; Berking, Carola; Horch, Raymund E.; Schett, Georg; Distler, Jörg H. W. & Bergmann, Christina
