Department of Biomedicine, Aarhus University, Aarhus DK-8000, Denmark.
Department of Biomedicine, Aarhus University, Aarhus DK-8000, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus DK-8000, Denmark; Department of Rheumatology, Aarhus University Hospital, Aarhus N 8200, Denmark.
EBioMedicine. 2021 Apr;66:103314. doi: 10.1016/j.ebiom.2021.103314. Epub 2021 Apr 2.
Nucleic acids are potent stimulators of type I interferon (IFN-I) and antiviral defense, but may also promote pathological inflammation. A range of diseases are characterized by elevated IFN-I, including systemic lupus erythematosus (lupus). The DNA-activated cGAS-STING pathway is a major IFN-I-inducing pathway, and activation of signaling is dependent on trafficking of STING from the ER to the Golgi.
Here we used cell culture systems, a mouse lupus model, and material from lupus patients, to explore the mode of action of a STING antagonistic peptide, and its ability to modulate disease processes.
We report that the peptide ISD017 selectively inhibits all known down-stream activities of STING, including IFN-I, inflammatory cytokines, autophagy, and apoptosis. ISD017 blocks the essential trafficking of STING from the ER to Golgi through a mechanism dependent on the STING ER retention factor STIM1. Importantly, ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. Finally, ISD017 treatment blocks pathological cytokine responses in cells from lupus patients with elevated IFN-I levels.
These data hold promise for beneficial use of STING-targeting therapy in lupus.
The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.
核酸是 I 型干扰素（IFN-I）和抗病毒防御的有效刺激物，但也可能促进病理性炎症。一系列疾病的特征是 IFN-I 升高，包括系统性红斑狼疮（狼疮）。DNA 激活的 cGAS-STING 途径是 IFN-I 诱导的主要途径，信号的激活依赖于 STING 从内质网到高尔基体的运输。
在这里，我们使用细胞培养系统、狼疮小鼠模型和狼疮患者的材料，探索了一种 STING 拮抗肽的作用模式及其调节疾病过程的能力。
我们报告该肽 ISD017 选择性抑制 STING 的所有已知下游活性，包括 IFN-I、炎性细胞因子、自噬和细胞凋亡。ISD017 通过一种依赖于 STING ER 保留因子 STIM1 的机制阻断 STING 从 ER 到高尔基体的必需运输。重要的是，ISD017 阻断了体内的 STING 活性，并改善了狼疮小鼠模型中的疾病发展。最后，ISD017 治疗阻断了 IFN-I 水平升高的狼疮患者细胞中病理性细胞因子反应。
这些数据为 STING 靶向治疗在狼疮中的有益应用带来了希望。
诺和诺德基金会、欧洲研究理事会、丹麦隆德贝克基金会、欧盟地平线 2020 研究计划、德国研究基金会、朱拉隆功大学。
