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红细胞线粒体滞留引发人类系统性红斑狼疮中髓细胞依赖性的I型干扰素
作者:小柯机器人 发布时间:2021/8/15 13:16:01

美国威尔康奈尔医学院Virginia Pascual、Simone Caielli等研究人员合作发现,红细胞线粒体滞留引发人类系统性红斑狼疮中髓细胞依赖性的I型干扰素。2021年8月11日,《细胞》杂志在线发表了这项成果。

研究人员表明,哺乳动物红细胞生成的标志——程序性线粒体清除在系统性红斑狼疮中是有缺陷的。具体来说,研究人员证明在人类红细胞成熟过程中,一个由缺氧诱导因子(HIF)介导的代谢开关负责激活泛素-蛋白酶体系统(UPS),该系统先于线粒体的自噬清除,并且是自噬清除的必要条件。

这一途径的缺陷导致系统性红斑狼疮患者体内携带线粒体红细胞(Mito+RBC)的积累,并与疾病活动相关。抗体介导的Mito+RBC內吞通过激活巨噬细胞中的cGAS来诱导I型干扰素(IFN)的产生。相应地,同时携带Mito+RBC和调理抗体的系统性红斑狼疮患者显示出最高水平的血液IFN刺激基因(ISG)特征,这是系统性红斑狼疮的一个明显特征。

据介绍,新的证据支持线粒体功能障碍有助于系统性红斑狼疮的发病机制。

附:英文原文

Title: Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE

Author: Simone Caielli, Jacob Cardenas, Adriana Almeida de Jesus, Jeanine Baisch, Lynnette Walters, Jean Philippe Blanck, Preetha Balasubramanian, Cristy Stagnar, Marina Ohouo, Seunghee Hong, Lorien Nassi, Katie Stewart, Julie Fuller, Jinghua Gu, Jacques F. Banchereau, Tracey Wright, Raphaela Goldbach-Mansky, Virginia Pascual

Issue&Volume: 2021-08-11

Abstract: Emerging evidence supports that mitochondrial dysfunction contributes to systemiclupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrialremoval, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically,we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor(HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasomesystem (UPS), which precedes and is necessary for the autophagic removal of mitochondria.A defect in this pathway leads to accumulation of red blood cells (RBCs) carryingmitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediatedinternalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages.Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulatedgene (ISG) signatures, a distinctive feature of SLE.

DOI: 10.1016/j.cell.2021.07.021

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00880-1

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/