NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment
NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment
复制标题
NSun2 通过促进自分泌运动因子表达和 T 细胞募集来调节动脉瘤形成
DOI：
10.1007/s00018-020-03607-7
复制
发表时间：
2020-07-30
影响因子：
8
通讯作者：
Feng, Juan
中科院分区：
文献类型：
--
作者：
Miao, Yutong;Zhao, Yang;Feng, Juan
腹主动脉瘤（AAA）以炎症细胞浸润为特征，且高同型半胱氨酸血症（HHcy）会使其病情加重。目前尚不清楚同型半胱氨酸（Hcy）激活的RNA甲基转移酶NOP2/Sun结构域家族成员2（NSun2）是否与AAA相关。在此，我们发现NSun2缺失可显著减轻弹性蛋白酶诱导及HHcy加重的小鼠AAA，同时血管壁中T细胞浸润减少。T细胞标记和过继转移实验证实，NSun2缺失抑制了血管对T细胞的趋化作用。内皮细胞的RNA测序显示，Hcy诱导了磷脂PC - LPC - LPA代谢途径中多种代谢酶的积累，尤其是自分泌运动因子（ATX）。在弹性蛋白酶诱导的AAA小鼠模型中，ATX在内皮细胞中特异性表达，血浆ATX浓度上调，在HHcy组中甚至更高，而NSun2基因敲低后这些指标显著下降。体外Transwell实验表明，ATX呈剂量依赖性促进T细胞迁移。HHcy可能上调内皮细胞ATX的表达和分泌，进而招募T细胞进入血管壁，引发血管炎症，从而加速AAA的发病进程。从机制上讲，分泌的ATX通过与整合素α4结合与T细胞相互作用，随后激活下游FAK/Src - RhoA信号通路，进而诱导T细胞趋化和黏附。血管壁中ATX过表达可逆转NSun2缺陷小鼠中AAA发展受抑制的情况。因此，NSun2主要通过增加内皮细胞ATX的表达、分泌以及T细胞迁移来介导HHcy加重的AAA的发展，这是HHcy加重血管炎症及AAA发病机制的一种新机制。
Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.