Apel Falko, Andreeva Liudmila, Knackstedt Lorenz Sebastian, Streeck Robert, Frese Christian Karl, Goosmann Christian, Hopfner Karl-Peter, Zychlinsky Arturo
Max Planck Institute for Infection Biology, Department of Cellular Microbiology, Charitéplatz 1, 10117 Berlin, Germany.
Department of Biology, Humboldt University, Charitéplatz 1, 10117 Berlin, Germany.
Sci Signal. 2021 Mar 9;14(673):eaax7942. doi: 10.1126/scisignal.aax7942.
Neutrophil extracellular traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation, and activate myeloid cells to produce type I interferons (IFNs), proinflammatory cytokines that regulate the immune system. Here, we showed that macrophages and other myeloid cells phagocytosed NETs. Once in phagosomes, NETs translocated to the cytosol, where the DNA backbones of these structures activated the innate immune sensor cyclic GMP-AMP synthase (cGAS) and induced type I IFN production. The NET-associated serine protease neutrophil elastase (NE) mediated the activation of this pathway. We showed that NET induction in mice treated with the lectin concanavalin A, a model of autoimmune hepatitis, resulted in cGAS-dependent stimulation of an IFN response, suggesting that NETs activated cGAS in vivo. Thus, our findings suggest that cGAS is a sensor of NETs, mediating immune cell activation during infection.
中性粒细胞胞外诱捕网（NETs）是由染色质和抗菌分子组成的结构，在一种称为NETosis的程序性细胞死亡过程中由中性粒细胞释放。NETs捕获入侵的病原体，促进凝血，并激活髓样细胞以产生I型干扰素（IFN），这是一类调节免疫系统的促炎细胞因子。在此，我们发现巨噬细胞和其他髓样细胞会吞噬NETs。一旦进入吞噬体，NETs就会转移到细胞质中，在那里这些结构的DNA骨架激活了天然免疫传感器环状GMP-AMP合酶（cGAS）并诱导I型干扰素的产生。与NET相关的丝氨酸蛋白酶中性粒细胞弹性蛋白酶（NE）介导了该途径的激活。我们发现，用凝集素伴刀豆球蛋白A（一种自身免疫性肝炎模型）处理的小鼠中NET的诱导导致了依赖cGAS的IFN反应刺激，这表明NETs在体内激活了cGAS。因此，我们的研究结果表明，cGAS是NETs的传感器，在感染期间介导免疫细胞激活。
