Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece.
Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece.
J Autoimmun. 2019 Nov;104:102327. doi: 10.1016/j.jaut.2019.102327. Epub 2019 Aug 28.
Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids including blood. ATX catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a growth factor-like, signaling phospholipid. LPA exerts pleiotropic effects mediated by its G-protein-coupled receptors that are widely expressed and exhibit overlapping specificities. Although ATX also possesses matricellular properties, the majority of ATX reported functions in adulthood are thought to be mediated through the extracellular production of LPA. ATX-mediated LPA synthesis is likely localized at the cell surface through the possible interaction of ATX with integrins or other molecules, while LPA levels are further controlled by a group of membrane-associated lipid-phosphate phosphatases. ATX expression was shown to be necessary for embryonic development, and ATX deficient embryos exhibit defective vascular homeostasis and aberrant neuronal system development. In adult life, ATX is highly expressed in the adipose tissue and has been implicated in diet-induced obesity and glucose homeostasis with multiple implications in metabolic disorders. Additionally, LPA has been shown to affect multiple cell types, including stromal and immune cells in various ways. Therefore, LPA participates in many processes that are intricately involved in the pathogenesis of different chronic inflammatory diseases such as vascular homeostasis, skeletal and stromal remodeling, lymphocyte trafficking and immune regulation. Accordingly, increased ATX and LPA levels have been detected, locally and/or systemically, in patients with chronic inflammatory diseases, most notably idiopathic pulmonary fibrosis (IPF), chronic liver diseases, and rheumatoid arthritis. Genetic and pharmacological studies in mice have confirmed a pathogenetic role for ATX expression and LPA signaling in chronic inflammatory diseases, and provided the proof of principle for therapeutic interventions, as exemplified by the ongoing clinical trials for IPF.
自分泌酶（Autotaxin，ATX）是一种分泌型糖蛋白，广泛存在于包括血液在内的生物体液中。ATX 催化溶血磷脂酰胆碱（Lysophosphatidylcholine，LPC）水解为溶血磷脂酸（Lysophosphatidic acid，LPA），LPA 是一种类似生长因子的信号磷脂。LPA 通过其广泛表达并具有重叠特异性的 G 蛋白偶联受体发挥多种效应。尽管 ATX 还具有基质细胞特性，但大多数在成年期报道的 ATX 功能被认为是通过细胞外产生 LPA 介导的。ATX 介导的 LPA 合成可能通过 ATX 与整合素或其他分子的可能相互作用而局部位于细胞表面，而 LPA 水平进一步受一组膜相关的脂质磷酸酶控制。ATX 表达被证明对胚胎发育是必需的，ATX 缺陷的胚胎表现出血管稳态缺陷和异常的神经元系统发育。在成年期，ATX 在脂肪组织中高度表达，并与饮食诱导的肥胖和葡萄糖稳态有关，在代谢紊乱中有多种影响。此外，LPA 已被证明以多种方式影响多种细胞类型，包括基质和免疫细胞。因此，LPA 参与许多复杂的过程，这些过程与不同慢性炎症性疾病的发病机制有关，如血管稳态、骨骼和基质重塑、淋巴细胞迁移和免疫调节。因此，在慢性炎症性疾病患者中，局部和/或全身检测到 ATX 和 LPA 水平升高，最明显的是特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）、慢性肝病和类风湿关节炎。在小鼠中的遗传和药理学研究证实了 ATX 表达和 LPA 信号在慢性炎症性疾病中的发病机制作用，并为治疗干预提供了原理证明，如正在进行的 IPF 临床试验。
