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

系统性硬化症（SSc）是一种典型的系统性纤维化疾病，细胞外基质在皮肤和其他受累器官中过度沉积。纤维化组织重塑对现代社会造成了重大负担，在西方社会可能导致高达45%的死亡。SSc和其他纤维化疾病的特点是成纤维细胞过度和持续激活。活化的成纤维细胞释放过量的细胞外基质，因此是纤维化组织纤维化的关键效应细胞。虽然转化生长因子-β (tgf -β)被认为是成纤维细胞活化和组织纤维化的核心途径，但tgf -β的下游介质及其在组织纤维化中的相互作用仍不完全清楚。我们的初步结果首次证明了G蛋白偶联受体激酶5 （GRK5）以tgf β依赖的方式在SSc成纤维细胞的细胞核中积累。GRK5过表达可促进静息成纤维细胞向肌成纤维细胞分化，而GRK5敲低可改善tgf β依赖性成纤维细胞活化和实验性皮肤纤维化。从机制上讲，GRK5可能作为多种纤维化机制的上游调节剂，包括组蛋白乙酰化和STAT3信号的调节。为了进一步阐明GRK5在TGFβ信号传导、成纤维细胞活化和组织纤维化中的作用，我们将分析GRK5的亚细胞定位与SSc患者临床特征之间的相关性，表征促进GRK5在SSc中核积累的分子过程，研究GRK5刺激成纤维细胞活化的机制，并在其他SSc小鼠模型中证实GRK5失活的抗纤维化作用。这些数据可能确立GRK5作为SSc抗纤维化治疗的靶点。

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.