Mederacke Ingmar, Filliol Aveline, Affo Silvia, Nair Ajay, Hernandez Celine, Sun Qiuyan, Hamberger Florian, Brundu Francesco, Chen Yu, Ravichandra Aashreya, Huebener Peter, Anke Helena, Shi Hongxue, Martínez García de la Torre Raquel A, Smith James R, Henderson Neil C, Vondran Florian W R, Rothlin Carla V, Baehre Heike, Tabas Ira, Sancho-Bru Pau, Schwabe Robert F
Department of Medicine, Columbia University, New York, NY 10032, USA.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
Sci Transl Med. 2022 Apr 6;14(639):eabe5795. doi: 10.1126/scitranslmed.abe5795.
Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although platelet-derived growth factor and transforming growth factor-β constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5'-diphosphate (UDP)-glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal-regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis.
在西方国家，纤维化导致约45%的死亡。在慢性肝病中，纤维化是决定预后的主要因素，但缺乏有效的抗纤维化疗法。尽管血小板衍生生长因子和转化生长因子-β是关键的促纤维化介质，但它们并不能解释肝脏中细胞死亡与纤维化之间已明确的联系。在此，我们假设损伤相关分子模式（DAMPs）可能将上皮细胞死亡与受损肝脏中的纤维化联系起来。DAMP受体筛选在多个候选受体中确定嘌呤能受体P2Y14在肝星状细胞（HSCs）中高度富集，肝星状细胞是肝脏主要的促纤维化细胞类型。相反，P2Y14配体尿苷5'-二磷酸（UDP）-葡萄糖和UDP-半乳糖在肝细胞中富集，并在不同的细胞死亡模式下释放。因此，结合蛋白质组学和单细胞RNA测序数据的配体-受体相互作用分析分别揭示P2Y14配体和P2Y14受体是死亡细胞与肝星状细胞之间的联系。用P2Y14配体处理或与死亡的肝细胞共培养以P2Y14依赖的方式促进肝星状细胞活化。P2Y14配体激活肝星状细胞中的细胞外信号调节激酶（ERK）和Yes相关蛋白（YAP）信号通路，导致ERK依赖的肝星状细胞活化。在多种肝损伤小鼠模型中，全身性和肝星状细胞选择性P2Y14缺陷减轻了肝纤维化。在健康和患病的人肝脏及人肝星状细胞中证实了P2Y14的功能性表达。总之，P2Y14配体及其受体构成了一条直接将细胞死亡与纤维化联系起来的促纤维化DAMP途径。
