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

Fibrotic diseases account for up to 45% of deaths in the developed world and impose a major socioeconomic burden on modern societies. Systemic sclerosis (SSc) is a prototypical idiopathic systemic fibrosing disease and is the autoimmune rheumatic disease with the highest case-specific morbidity. The central histopathological feature of SSc is the excessive accumulation of extracellular matrix, which is caused by increased release from persistently activated fibroblasts. The molecular mechanisms underlying this pathologic activation of fibroblasts are not well understood and as a consequence, targeted therapies are not available for the treatment of fibrosis in SSc. Our preliminary results demonstrate that Wnt5a is overexpressed in fibroblasts of SSc patients in vitro and in vivo and that this overexpression of Wnt5a is mimicked in murine models of SSc. In contrast to Wnt5a, other ligands of non-canonical Wnt-signaling are not overexpressed in SSc. Wnt5a potently activates fibroblasts and stimulates myofibroblast differentiation and collagen release. The pro-fibrotic effects of Wnt5a depend on activation of JNK and cJun and inactivation of JNK or cJun completely abrogates these stimulatory effects. Overexpression of Wnt5a in the skin of mice induces prominent fibrosis, whereas fibroblast-specific knockout of Wnt5a protects from experimental skin fibrosis. In the proposed project, we will generate expression profiles of all known receptors of Wnt5a and demonstrate their functional role by targeting them in vitro and in vivo. Moreover, we will identify the factors and intracellular mediators that drive the overexpression of Wnt5a in SSc and in experimental fibrosis. We will also characterize the molecular mechanisms by which PCP signaling regulates the transcription of pro-fibrotic genes. Finally, we will extend our findings on the pro-fibrotic effects of Wnt5a from SSc to other fibrotic diseases and evaluate the anti-fibrotic effects of targeting Wnt5a-induced non-canonical Wnt signaling in murine models of idiopathic pulmonary fibrosis and sclerodermatous chronic graft-versus-host disease.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Alfiya Akhmetshina-Distler, Ph.D., until 6/2017