Wnt5a activates fibroblasts and induces fibrosis via the planar cell polarity pathway

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler, since 6/2017
• Subject Area: Rheumatology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283389830

• Final Report Year: 2021

Final Report Abstract

Wir konnten zeigen, dass WNT5A über eine ITGAV-abhängige Aktivierung von latentem TGFß eine Differenzierung von ruhenden Fibroblasten in Myofibroblasten induziert und alleine suffizient ist, um Fibrose zu induzieren. Diese profibrotischen Effekte werden über ROR2- und RYK-Rezeptoren sowie über ROCK- und JNK-Kinasen vermittelt. Die Hemmung dieser Signalkaskade, durch Knockout von WNT5A, durch ROCK- oder JNK-Inhibitoren, oder durch Überexpression eines ROR2-Fc-Decoy Rezeptors hemmen Fibrose in verschiedenen Mausmodellen.

Publications

• Activation of Signal Transducer and Activator of Transcription 3 (STAT3) integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun. 2017 Oct 24;8(1):1130
  Chakraborty, Debomita; Šumová, Barbora; Mallano, Tatjana; Chen, Chih-Wei; Distler, Alfiya; Bergmann, Christina; Ludolph, Ingo; Horch, Raymund E.; Gelse, Kolja; Ramming, Andreas; Distler, Oliver; Schett, Georg; Šenolt, Ladislav & Distler, Jörg H. W.
  
• JAK1-dependent transphosphorylation of JAK2 limits the anti-fibrotic effects of selective JAK2 inhibitors upon long-term treatment. Ann Rheum Dis. 2017 Aug;76(8):1467-1475
  Zhang, Yun; Liang, Ruifang; Chen, Chih-Wei; Mallano, Tatjana; Dees, Clara; Distler, Alfiya; Reich, Adam; Bergmann, Christina; Ramming, Andreas; Gelse, Kolja; Mielenz, Dirk; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Nintedanib macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis., Ann Rheum Dis. 2017 Aug 16
  Huang, Jingang; Maier, Christiane; Zhang, Yun; Soare, Alina; Dees, Clara; Beyer, Christian; Harre, Ulrike; Chen, Chih-Wei; Distler, Oliver; Schett, Georg; Wollin, Lutz & Distler, Jörg H. W.
  
• Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators. Ann Rheum Dis. 2018 Jan 8
  Matei, Alexandru-Emil; Beyer, Christian; Györfi, Andrea-Hermina; Soare, Alina; Chen, Chih-Wei; Dees, Clara; Bergmann, Christina; Ramming, Andreas; Friebe, Andreas; Hofmann, Franz; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis. 2017 Oct 25
  Bergmann, Christina; Brandt, Amelie; Merlevede, Benita; Hallenberger, Ludwig; Dees, Clara; Wohlfahrt, Thomas; Pötter, Sebastian; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatiana; Liang, Ruifang; Kagwiria, Rosebeth; Kreuter, Alexander; Pantelaki, Ioanna; Bozec
  
• PU.1 controls fibroblast polarization and tissue fibrosis. Nature. 2019 Jan 30
  Wohlfahrt, Thomas; Rauber, Simon; Uebe, Steffen; Luber, Markus; Soare, Alina; Ekici, Arif; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Maier, Christiane; Karouzakis, Emmanuel; Kiener, Hans P.; Pachera, Elena; Dees, Clara; Beyer, Christian; Daniel, Christoph; Gelse, Kolja; Kremer, Andreas E.; Naschberger, Elisabeth; ... & Ramming, Andreas
  
• TGFβ-induced epigenetic deregulation of SOCS3 facilitates STAT3-signaling to promote fibrosis. J Clin Invest. 2020 May 1;130(5):2347-2363
  Dees, Clara; Pötter, Sebastian; Zhang, Yun; Bergmann, Christina; Zhou, Xiang; Luber, Markus; Wohlfahrt, Thomas; Karouzakis, Emmanuel; Ramming, Andreas; Gelse, Kolja; Yoshimura, Akihiko; Jaenisch, Rudolf; Distler, Oliver; Schett, Georg & Distler, Jörg H.W.