Gentile Daniela, Lazzerini Pietro E, Gamberucci Alessandra, Natale Mariarita, Selvi Enrico, Vanni Francesca, Alì Alessandra, Taddeucci Paolo, Del-Ry Silvia, Cabiati Manuela, Della-Latta Veronica, Abraham David J, Morales Maria A, Fulceri Rosella, Laghi-Pasini Franco, Capecchi Pier L
Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Front Pharmacol. 2017 Sep 13;8:638. doi: 10.3389/fphar.2017.00638. eCollection 2017.
Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways. Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated. P2X7R expression and Ca permeability induced by the selective P2X7R agonist 2'-3'-O-(4-benzoylbenzoyl)ATP (BzATP) were markedly higher in SSc than control fibroblasts. Moreover, increased αSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway. In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc.
系统性硬化症（SSc）是一种结缔组织疾病，表现为皮肤和内脏器官纤维化，目前尚无有效的治疗方法。越来越多的证据表明，P2X7受体（P2X7R）是一种主要参与炎症反应的核苷酸门控离子通道，在不同身体部位的组织纤维化发展中可能也起着关键作用。本研究旨在调查P2X7R在促进SSc患者真皮成纤维细胞纤维化表型中的表达和功能，同时分析潜在的机制途径。通过皮肤活检从9例SSc患者和8例健康对照中分离出成纤维细胞。研究了P2X7R的表达和功能（胞质游离钙通量、α-平滑肌肌动蛋白[α-SMA]表达、细胞迁移和胶原蛋白释放）。此外，评估了细胞因子（白细胞介素-1β、白细胞介素-6）和结缔组织生长因子（CTGF）的产生以及细胞外信号调节激酶（ERK）激活在介导SSc成纤维细胞中P2X7R依赖性促纤维化作用中的作用。与对照成纤维细胞相比，SSc成纤维细胞中P2X7R的表达以及由选择性P2X7R激动剂2'-3'-O-（4-苯甲酰苯甲酰）ATP（BzATP）诱导的钙通透性明显更高。此外，在BzATP刺激后，在脂多糖预处理的SSc成纤维细胞中观察到αSMA表达增加、细胞迁移、CTGF和胶原蛋白释放增加。虽然P2X7诱导细胞因子变化不影响胶原蛋白产生，但ERK途径的抑制可完全消除这种作用。在SSc成纤维细胞中，P2X7R过表达，其刺激诱导钙信号激活和以迁移增加和胶原蛋白产生增加为特征的纤维化表型。这些数据表明P2X7R是控制SSc患者过度胶原蛋白沉积和组织纤维化的潜在新治疗靶点。
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