GRK5 as a multimodal regulator of TGFβ-dependent fibroblast activation in systemic sclerosis

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler
• Subject Area: Rheumatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461126449

Systemic Sclerosis (SSc) is a prototypical systemic fibrotic disease with excessive deposition of extracellular matrix in the skin and other affected organs. Fibrotic tissue remodeling imposes a major burden on modern societies and may contribute to up to 45% of deaths in Western societies. SSc and other fibrotic diseases are characterized by excessive and persistent activation of fibroblasts. Activated fibroblasts release excessive amounts of extracellular matrix and are thus key-effector cells of fibrotic tissue fibrosis. Although transforming growth factor-β (TGFβ) has been characterized as a core pathway of fibroblast activation and tissue fibrosis, the downstream mediators of TGFβ and their interplay in the context of tissue fibrosis remain incompletely understood. Our preliminary results provide first evidence that G protein-coupled receptor kinases 5 (GRK5) accumulates in the nucleus of SSc fibroblasts in a TGFβ-dependent manner. Overexpression of GRK5 promotes differentiation of resting fibroblasts into myofibroblasts, whereas knockdown of GRK5 ameliorates TGFβ-dependent fibroblast activation and experimental skin fibrosis. Mechanistically, GRK5 might serve as upstream regulator of multiple profibrotic mechanisms including modulation of histone acetylation and STAT3 signaling. To further decipher the role of GRK5 in TGFβ signaling, fibroblast activation and tissue fibrosis, we will analyze correlations between the subcellular localization of GRK5 and clinical characteristics of SSc patients, characterize the molecular processes that promote nuclear accumulation of GRK5 in SSc, investigate the mechanisms underlying the stimulatory effects of GRK5 on fibroblast activation and confirm the antifibrotic effects of GRK5 inactivation in additional mouse models of SSc. These data may establish GRK5 as a target for antifibrotic therapies in SSc.

• DFG Programme: Research Grants