Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.
Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.
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DOI：
10.3389/fimmu.2020.554725
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发表时间：
2020
影响因子：
7.3
通讯作者：
Arditi M
中科院分区：
文献类型：
--
作者：
Tumurkhuu G;Chen S;Montano EN;Ercan Laguna D;De Los Santos G;Yu JM;Lane M;Yamashita M;Markman JL;Blanco LP;Kaplan MJ;Shimada K;Crother TR;Ishimori M;Wallace DJ;Jefferies CA;Arditi M
系统性红斑狼疮（SLE）是一种慢性炎症性自身免疫性疾病，其中I型干扰素（IFN）起关键作用。当氧化的DNA与细胞溶质DNA传感平台cGAS-STING接合时，可以触发IFN应答，但调节这一过程并控制疾病进展的修复机制尚不清楚。为了深入了解这种生物学，我们研究了氧鸟嘌呤糖基化酶1（OGG 1）在降植烷诱导的SLE小鼠模型中的作用，该酶修复氧化的鸟嘌呤8-氧代-2 ′-脱氧鸟苷（8-OH-dG）。Ogg 1 −/−小鼠表现出Ly 6Chi单核细胞流入腹膜腔的增加，并增强了IFN驱动的基因表达，以响应短期暴露于降植烷。Ogg 1的丢失与自身抗体（抗dsDNA和抗RNP）增加、总IgG升高和干扰素刺激基因（ISG）表达延长暴露于降植烷相关，并伴有皮肤病理学恶化，如脱发、表皮增厚和皮肤病变中IgG沉积增加。支持I型IFN在该模型中的作用，Ogg 1 −/−小鼠的皮肤病变具有显著更高的I型IFN基因（Isg 15，Irf 9和Ifnb）表达。与Ogg 1缺失导致IFN应答失调一致，在Ogg 1 −/−小鼠的BMDM中观察到基础和cGAMP依赖性Ifnb表达增强。STING抑制剂H151的使用减少了基础和cGAMP驱动的增加，表明OGG 1通过cGAS-STING途径调节Ifnb表达。最后，为了支持OGG 1在皮肤疾病病理学中的作用，SLE患者中与皮肤受累相关的单核细胞中OGG 1表达降低，并且盘状狼疮患者中与非病变皮肤相比，病变皮肤中OGG 1的表达显著降低。总之，这些数据支持OGG 1在保护免受IFN产生和SLE皮肤病中的重要作用。
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2′-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1−/− mice showed increased influx of Ly6Chi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1−/− mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1−/− mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
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影响因子：
5.4
作者：
Bhat N;Fitzgerald KA
通讯作者：
Fitzgerald KA
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.
影响因子：
27.4
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
通讯作者：
Kumanogoh A
环状GMP-AMP合酶通过双链DNA诱导的寡聚化激活。
影响因子：
32.4
作者：
Li, Xin;Shu, Chang;Yi, Guanghui;Chaton, Catherine T.;Shelton, Catherine L.;Diao, Jiasheng;Zuo, Xiaobing;Kao, C. Cheng;Herr, Andrew B.;Li, Pingwei
通讯作者：
Li, Pingwei