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 D, Šumová B, Mallano T, Chen CW, Distler A, Bergmann C, Ludolph I, Horch RE, Gelse K, Ramming A, Distler O, Schett G, Šenolt L, Distler JH
  (See online at https://doi.org/10.1038/s41467-017-01236-6)
• 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 Y, Liang R, Chen C-W, Mallano T, Dees C, Distler A, Reich A, Bergmann C, Ramming A, Gelse K, Milenz D, Distler O,Schett G, Distler JH
  (See online at https://doi.org/10.1136/annrheumdis-2016-210911)
• 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 J, Maier C, Zhang Y, Soare A, Dees C, Beyer C, Harre U, Chen C-W, Distler O, Schett G, Wollin L, Distler JH
  (See online at https://doi.org/10.1136/annrheumdis-2016-210823)
• The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis. 2017 Oct 25
  Bergmann C, Brandt A, Merlevede B, Hallenberger L, Dees C, Wohlfahrt T, Pötter S, Zhang Y, Chen CW, Mallano T, Liang R, Kagwiria R, Kreuter A, Pantelaki I, Bozec A, Abraham D, Rieker R, Ramming A, Distler O, Schett G, Distler JHW
  (See online at https://doi.org/10.1136/annrheumdis-2017-211501)
• Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators. Ann Rheum Dis. 2018 Jan 8
  Matei AE, Beyer C, Györfi AH, Soare A, Chen CW, Dees C, Bergmann C, Ramming A, Friebe A, Hofmann F, Distler O, Schett G, Distler JHW
  (See online at https://doi.org/10.1136/annrheumdis-2017-212489)
• PU.1 controls fibroblast polarization and tissue fibrosis. Nature. 2019 Jan 30
  Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici A, Weber S, Matei AE, Chen CW, Maier C, Karouzakis E, Kiener HP, Pachera E, Dees C, Beyer C, Daniel C, Gelse K, Kremer AE, Naschberger E, Stürzl M, Butter F, Sticherling M, Finotto S, Kreuter A, Kaplan MH, Jüngel A, Gay S, Nutt SL, Boykin DW, Poon GMK, Distler O, Schett G, Distler JHW, Ramming A
  (See online at https://doi.org/10.1038/s41586-019-0896-x)
• TGFβ-induced epigenetic deregulation of SOCS3 facilitates STAT3-signaling to promote fibrosis. J Clin Invest. 2020 May 1;130(5):2347-2363
  Dees C, Pötter S, Zhang Y, Bergmann C, Zhou X, Luber M, Wohlfahrt T, Karouzakis E, Ramming A, Gelse K, Yoshimura A, Jaenisch R, Distler O, Schett G, Distler JHW
  (See online at https://doi.org/10.1172/JCI122462)