STING manifests self DNA-dependent inflammatory disease
STING manifests self DNA-dependent inflammatory disease
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DOI：
10.1073/pnas.1215006109
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发表时间：
2012-11-20
影响因子：
11.1
通讯作者：
Barber, Glen N.
中科院分区：
文献类型：
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作者：
Ahn, Jeonghyun;Gutman, Delia;Barber, Glen N.
炎症性自身免疫性疾病如系统性红斑狼疮（SLE）和多发性关节炎的特征在于慢性细胞因子过度产生，这表明推测通过持续感染或自身核酸刺激宿主先天免疫应答在这些疾病的表现中起作用。缺乏DNase II的小鼠在胚胎发育期间通过类似的炎性疾病死亡，因为来自凋亡细胞的吞噬DNA不能被充分消化，并且细胞内宿主DNA传感器途径参与，导致产生多种细胞因子，包括I型IFN。负责触发DNA介导的炎症加重自身免疫性疾病的细胞传感器通路仍有待确定。然而，我们在这里报告，刺激因子IFN基因（STING）是负责炎症相关的胚胎死亡的DNase II缺陷小鼠启动的自我DNA。DNA酶II依赖性胚胎致死性通过STING功能的丧失而被挽救，并且多关节炎完全被预防，因为胞质DNA未能通过STING控制的信号传导途径稳健地触发细胞因子产生。我们的数据为DNA介导的炎症性疾病的病因提供了重要的分子见解，并提供了一个可以在治疗上控制以帮助预防此类疾病的靶点。
Inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and polyarthritis are characterized by chronic cytokine overproduction, suggesting that the stimulation of host innate immune responses, speculatively by persistent infection or self nucleic acids, plays a role in the manifestation of these disorders. Mice lacking DNase II die during embryonic development through comparable inflammatory disease because phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensor pathways are engaged, resulting in the production of a variety of cytokines including type I IFN. The cellular sensor pathway(s) responsible for triggering DNA-mediated inflammation aggravated autoimmune disease remains to be determined. However, we report here that Stimulator of IFN Genes (STING) is responsible for inflammation-related embryonic death in DNase II defective mice initiated by self DNA. DNase II-dependent embryonic lethality was rescued by loss of STING function, and polyarthritis completely prevented because cytosolic DNA failed to robustly trigger cytokine production through STING-controlled signaling pathways. Our data provides significant molecular insight into the causes of DNA-mediated inflammatory disorders and affords a target that could plausibly be therapeutically controlled to help prevent such diseases.