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STING controls nociception via type I interferon signalling in sensory neurons
Nature ( IF 42.778 ) Pub Date : 2021-01-13 , DOI: 10.1038/s41586-020-03151-1
Christopher R. Donnelly; Changyu Jiang; Amanda S. Andriessen; Kaiyuan Wang; Zilong Wang; Huiping Ding; Junli Zhao; Xin Luo; Michael S. Lee; Yu L. Lei; William Maixner; Mei-Chuan Ko; Ru-Rong Ji

The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells1,2. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy3. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells4,5. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING–IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.



中文翻译:

STING通过I型干扰素信号传导控制感觉神经元的伤害感受

先天性免疫调节剂STING是自身和病原体DNA的关键传感器。通过STING的DNA感应导致诱导I型干扰素(IFN-I)和其他细胞因子,从而促进免疫细胞介导的病原体和肿瘤细胞1,2的根除。STING还是抗肿瘤免疫力的强大驱动力,这导致了STING激活剂和小分子激动剂作为癌症免疫疗法的佐剂的发展3。疼痛由周围伤害性感觉神经元(伤害感受器)传播,还通过提醒生物体存在潜在的破坏性刺激物(包括病原体和癌细胞)来帮助宿主防御4,5。在这里,我们证明STING是外周伤害感受器中通过IFN-I信号传导的伤害感受的关键调节剂。我们显示,缺少STING或IFN-I信号传导的小鼠表现出对伤害性刺激的超敏性,并增强了伤害性受体的兴奋性。相反,鞘内激活STING在小鼠和非人类灵长类动物中产生强大的抗伤害感受。STING介导的抗伤害感受作用受IFN-Is的控制,后者可迅速抑制小鼠,猴子和人类伤害感受器的兴奋性。我们的发现将STING–IFN-I信号轴确立为生理伤害感受的关键调节器,并有望成为治疗慢性疼痛的新靶标。

更新日期:2021-01-13
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