Apoptosis-derived membrane vesicles drive the cGAS-STING pathway and enhance type I IFN production in systemic lupus erythematosus.
Apoptosis-derived membrane vesicles drive the cGAS-STING pathway and enhance type I IFN production in systemic lupus erythematosus.
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DOI：
10.1136/annrheumdis-2018-212988
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发表时间：
2018-10
影响因子：
27.4
通讯作者：
Kumanogoh A
中科院分区：
文献类型：
--
作者：
Kato Y;Park J;Takamatsu H;Konaka H;Aoki W;Aburaya S;Ueda M;Nishide M;Koyama S;Hayama Y;Kinehara Y;Hirano T;Shima Y;Narazaki M;Kumanogoh A
尽管I型干扰素(IFN-I)在系统性红斑狼疮(SLE)发病机制中占有重要地位，但其产生机制尚未完全阐明。DNA传感器对核酸的识别可诱导干扰素-I和干扰素刺激基因(ISGs)，但环鸟苷单磷酸(GMP)-AMP合成酶(CGAS)和干扰素基因刺激物(STING)在SLE中的作用尚不清楚。我们研究了cGAS-STING通路在SLE血清驱动的干扰素-I产生级联反应中的作用。我们收集了系统性红斑狼疮患者(n=)、其他自身免疫性疾病患者(n=31)和健康对照组(n=35)的血清，并使用基于细胞的报告系统进行了检测，该系统能够高度灵敏地检测干扰素-I和胰岛素样生长因子诱导活性。我们使用Toll样受体特异性报告细胞和含有cGAS、STING和IFNAR2基因敲除的报告细胞来评估依赖信号通路的ISG诱导。SLE患者血清中的干扰素-I生物活性和ISG诱导活性均高于其他自身免疫性疾病患者和健康对照组。在基因敲除的报告细胞中，SLE血清的ISG诱导活性显著降低，且依赖于STING的ISG诱导活性与疾病活动性相关。SLE患者双链DNA水平升高。从SLE血清中提取的凋亡衍生膜小泡(AdMvs)具有较高的ISG诱导活性，而在cGAS基因敲除或刺伤基因敲除的报告细胞中，这种诱导活性减弱。SLE血清中的AdMv通过激活cGAS-STING途径诱导干扰素-I的产生。因此，阻断cGAS刺轴是治疗SLE的一个很有前途的靶点。此外，我们的基于细胞的报告系统可能有助于对具有高ISG诱导活性的SLE患者进行分层。
Despite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)–AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS–STING pathway in the IFN-I-producing cascade driven by SLE serum. We collected sera from patients with SLE (n=64), patients with other autoimmune diseases (n=31) and healthy controls (n=35), and assayed them using a cell-based reporter system that enables highly sensitive detection of IFN-I and ISG-inducing activity. We used Toll-like receptor-specific reporter cells and reporter cells harbouring knockouts of cGAS, STING and IFNAR2 to evaluate signalling pathway-dependent ISG induction. IFN-I bioactivity and ISG-inducing activities of serum were higher in patients with SLE than in patients with other autoimmune diseases or healthy controls. ISG-inducing activity of SLE sera was significantly reduced in STING-knockout reporter cells, and STING-dependent ISG-inducing activity correlated with disease activity. Double-stranded DNA levels were elevated in SLE. Apoptosis-derived membrane vesicles (AdMVs) from SLE sera had high ISG-inducing activity, which was diminished in cGAS-knockout or STING-knockout reporter cells. AdMVs in SLE serum induce IFN-I production through activation of the cGAS–STING pathway. Thus, blockade of the cGAS–STING axis represents a promising therapeutic target for SLE. Moreover, our cell-based reporter system may be useful for stratifying patients with SLE with high ISG-inducing activity.
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影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
13.3
作者：
An, Jie;Durcan, Laura;Elkon, Keith B.
通讯作者：
Elkon, Keith B.
系统性红斑狼疮
影响因子：
81.5
作者：
Kaul, Arvind;Gordon, Caroline;Hughes, Graham
通讯作者：
Hughes, Graham
影响因子：
15.9
作者：
Jeremiah, Nadia;Neven, Benedicte;Rieux-Laucat, Frederic
通讯作者：
Rieux-Laucat, Frederic