Table_6_PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1.xlsx

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and excessive fibrosis of the skin and internal organs. To this day, no effective treatments to prevent the progression of fibrosis exist, and SSc patients have disabilities and reduced life expectancy. The need to better understand pathways that drive SSc and to find therapeutic targets is urgent. RNA sequencing data from SSc dermal fibroblasts suggested that melanin-concentrating hormone receptor 1 (MCHR1), one of the G protein-coupled receptors regulating emotion and energy metabolism, is abnormally deregulated in SSc. Platelet-derived growth factor (PDGF)-BB stimulation upregulated MCHR1 mRNA and protein levels in normal human dermal fibroblasts (NHDF), and MCHR1 silencing prevented the PDGF-BB-induced expression of the profibrotic factors transforming growth factor beta 1 (TGFβ1) and connective tissue growth factor (CTGF). PDGF-BB bound MCHR1 in membrane fractions of NHDF, and the binding was confirmed using surface plasmon resonance (SPR). MCHR1 inhibition blocked PDGF-BB modulation of intracellular cyclic adenosine monophosphate (cAMP). MCHR1 silencing in NHDF reduced PDGF-BB signaling. In summary, MCHR1 promoted the fibrotic response in NHDF through modulation of TGFβ1 and CTGF production, intracellular cAMP levels, and PDGF-BB-induced signaling pathways, suggesting that MCHR1 plays an important role in mediating the response to PDGF-BB and in the pathogenesis of SSc. Inhibition of MCHR1 should be considered as a novel therapeutic strategy in SSc-associated fibrosis.

系统性硬化症（Systemic sclerosis, SSc）是一类以血管病变及皮肤、内脏器官过度纤维化为特征的自身免疫性疾病。时至今日，尚无有效治疗手段可阻断纤维化进展，SSc患者常伴随残疾且寿命缩短。深入解析驱动SSc发病的信号通路并发掘治疗靶点的需求极为迫切。来自SSc皮肤成纤维细胞的RNA测序数据显示，黑色素浓集激素受体1（melanin-concentrating hormone receptor 1, MCHR1）——一种调控情绪与能量代谢的G蛋白偶联受体（G protein-coupled receptor）——在SSc中存在异常失调。血小板衍生生长因子（platelet-derived growth factor, PDGF）-BB刺激可上调正常人体皮肤成纤维细胞（normal human dermal fibroblasts, NHDF）中MCHR1的mRNA与蛋白表达水平，而沉默MCHR1可阻断PDGF-BB诱导的促纤维化因子转化生长因子β1（transforming growth factor beta 1, TGFβ1）与结缔组织生长因子（connective tissue growth factor, CTGF）的表达。PDGF-BB可结合NHDF膜组分中的MCHR1，该结合相互作用经表面等离子体共振（surface plasmon resonance, SPR）得以验证。MCHR1抑制可阻断PDGF-BB对细胞内环磷酸腺苷（cyclic adenosine monophosphate, cAMP）的调控。在NHDF中沉默MCHR1可减弱PDGF-BB介导的细胞信号通路。综上，MCHR1通过调控TGFβ1与CTGF的产生、细胞内cAMP水平及PDGF-BB诱导的信号通路，促进NHDF的纤维化反应，提示MCHR1在介导PDGF-BB应答及SSc发病机制中发挥关键作用。应将MCHR1抑制视为SSc相关纤维化的新型治疗策略。