The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps
The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps
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DOI：
10.1126/scisignal.aax7942
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发表时间：
2021-03-09
影响因子：
7.3
通讯作者：
Zychlinsky, Arturo
中科院分区：
文献类型：
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作者：
Apel, Falko;Andreeva, Liudmila;Zychlinsky, Arturo
中性粒细胞胞外陷阱（NETs）是由染色质和抗菌分子组成的结构，在一种称为NETosis的调节性细胞死亡形式期间由中性粒细胞释放。NET捕获入侵的病原体，促进凝血，并激活骨髓细胞产生I型干扰素（IFN），调节免疫系统的促炎细胞因子。在这里，我们发现巨噬细胞和其他骨髓细胞吞噬NET。一旦在吞噬体中，NET易位到胞质溶胶，在那里这些结构的DNA骨架激活先天免疫传感器环GMP-AMP合酶（cGAS）并诱导I型IFN产生。NET相关的丝氨酸蛋白酶中性粒细胞弹性蛋白酶（NE）介导的激活这一途径。我们发现，在用凝集素伴刀豆球蛋白A（自身免疫性肝炎模型）治疗的小鼠中，NET诱导导致cGAS依赖性刺激IFN应答，表明NET在体内激活cGAS。因此，我们的研究结果表明，cGAS是NET的传感器，在感染期间介导免疫细胞活化。
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.