Triggering of the cGAS-STING Pathway in Human Plasmacytoid Dendritic Cells Inhibits TLR9-Mediated IFN Production
Triggering of the cGAS-STING Pathway in Human Plasmacytoid Dendritic Cells Inhibits TLR9-Mediated IFN Production
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DOI：
10.4049/jimmunol.1800933
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发表时间：
2020-07-01
影响因子：
4.4
通讯作者：
Fitzgerald-Bocarsly, Patricia
中科院分区：
文献类型：
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作者：
Deb, Pratik;Dai, Jihong;Fitzgerald-Bocarsly, Patricia
浆细胞样树突状细胞（pDC）是I型和III型IFN的有效生产者，并且在抗病毒免疫和自身免疫性疾病中起主要作用。核酸的先天感应仍然是pDC产生IFN的主要起始因素。已经详细研究和记录了TLR介导的经由内体途径的核酸感测，而人pDC中的胞质区室中的DNA感测仍然相对未被探索。我们现在证明了细胞溶质DNA传感途径的组分的存在和功能性，所述组分包括人pDC中的环GMP-AMP（cGAMP）合酶（cGAS）和IFN基因的刺激物（STING）。cGAS最初位于pDC的胞质区室中，并且与非CpG双链免疫刺激DNA（ISD）时间依赖性地共定位。在ISD与cGAS共定位后，随着STING从其在内质网的位置解离，下游途径被触发。在通过STING激动剂2 '3' cGAMP或dsDNA直接刺激pDC后，pDC-s产生I型和III型IFN。此外，我们记录了cGAS-STING介导的IFN产生是由IRF 3的核转位介导的，而TLR 9介导的激活通过IRF 7发生。我们的数据还表明cGAS-STING的pDC预刺激抑制了TLR 9介导的IFN产生。此外，触发cGAS-STING诱导pDC中SOCS 1和SOCS 3的表达，表明可能存在阻碍pDC产生IFN的自抑制环。因此，我们的研究表明，cGAS-STING途径与人pDC中TLR 9介导的DNA识别平行存在，这两种途径之间存在串扰。
Plasmacytoid dendritic cells (pDCs) are potent producers of type I and type III IFNs and play a major role in antiviral immunity and autoimmune disorders. The innate sensing of nucleic acids remains the major initiating factor for IFN production by pDCs. TLR-mediated sensing of nucleic acids via endosomal pathways has been studied and documented in detail, whereas the sensing of DNA in cytosolic compartment in human pDCs remains relatively unexplored. We now demonstrate the existence and functionality of the components of cytosolic DNA-sensing pathway comprising cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of IFN gene (STING) in human pDCs. cGAS was initially located in the cytosolic compartment of pDCs and time-dependently colocalized with non-CpG double-stranded immunostimulatory DNA (ISD). Following the colocalization of ISD with cGAS, the downstream pathway was triggered as STING disassociated from its location at the endoplasmic reticulum. Upon direct stimulation of pDCs by STING agonist 2'3' cGAMP or dsDNA, pDC-s produced type I, and type III IFN. Moreover, we documented that cGAS-STING-mediated IFN production is mediated by nuclear translocation of IRF3 whereas TLR9-mediated activation occurs through IRF7. Our data also indicate that pDC prestimulation of cGAS-STING dampened the TLR9-mediated IFN production. Furthermore, triggering of cGAS-STING induced expression of SOCS1 and SOCS3 in pDCs, indicating a possible autoinhibitory loop that impedes IFN production by pDCs. Thus, our study indicates that the cGAS-STING pathway exists in parallel to the TLR9-mediated DNA recognition in human pDCs with cross-talk between these two pathways.