Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
Rheumatology (Oxford). 2020 Oct 1;59(10):2992-3002. doi: 10.1093/rheumatology/keaa060.
Increased IFNα is important in the pathogenesis of SLE. Plasmacytoid dendritic cells are considered the main producer of IFNα upon Toll-like receptor pathway activation. However, which cells produce IFNα following stimulation with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) in SLE remains unknown. We investigated the IFNα producing capacity of myeloid cells under cGAS-STING pathway stimulation.
IFNα levels in peripheral blood mononuclear cells from SLE patients and healthy controls stimulated with 2'3'c-GAMP, a stimulator of cGAS-STING, were measured by intracellular cytokine staining and flow cytometry. STING expression and its co-localization with TBK1 were examined by flow cytometry or confocal microscopy. The effects of in vitro exposure to IFNα on IFNα production and STING expression, and in vitro rapamycin treatment on IFNα production and STING, pTBK1 and IRF3 expression were examined.
IFNα was produced by monocytes, conventional dendritic cells and plasmacytoid dendritic cells upon cGAS-STING pathway activation. The frequency of IFNα-producing monocytes positively correlated with SLE disease activity. STING expression and its co-localization with TBK1 were increased in lupus monocytes. Prior exposure to IFNα enhanced the IFNα-producing capacity of monocytes. Inhibition of the mechanistic target of the rapamycin (mTOR) pathway suppressed IFNα production from monocytes and downregulated enhanced STING expression and its downstream molecules.
Enhanced IFNα from lupus monocytes induced by augmented STING pathway activation is associated with SLE pathogenesis. Suppression of the mTOR pathway downregulated the enhanced STING expression and the subsequent IFNα production by monocytes.
IFNα 的增加在 SLE 的发病机制中很重要。浆细胞样树突状细胞被认为是 Toll 样受体途径激活后 IFNα 的主要产生细胞。然而，在 SLE 中，哪种细胞在环鸟苷酸-腺苷酸合酶（cGAS）和干扰素基因刺激物（STING）刺激后产生 IFNα 尚不清楚。我们研究了 cGAS-STING 途径刺激下髓样细胞产生 IFNα 的能力。
通过细胞内细胞因子染色和流式细胞术测量 SLE 患者和健康对照者外周血单个核细胞在 2'3'c-GAMP（cGAS-STING 的刺激物）刺激下的 IFNα 水平。通过流式细胞术或共聚焦显微镜检查 STING 表达及其与 TBK1 的共定位。检查体外暴露于 IFNα 对 IFNα 产生和 STING 表达的影响，以及体外雷帕霉素处理对 IFNα 产生和 STING、pTBK1 和 IRF3 表达的影响。
cGAS-STING 途径激活后，单核细胞、常规树突状细胞和浆细胞样树突状细胞产生 IFNα。IFNα 产生单核细胞的频率与 SLE 疾病活动呈正相关。狼疮单核细胞中 STING 表达及其与 TBK1 的共定位增加。先前暴露于 IFNα 增强了单核细胞产生 IFNα 的能力。雷帕霉素（mTOR）途径的抑制抑制了单核细胞产生 IFNα，并下调了增强的 STING 表达及其下游分子。
增强的 STING 途径激活引起的狼疮单核细胞中增强的 IFNα与 SLE 的发病机制有关。mTOR 途径的抑制下调了增强的 STING 表达及其随后的单核细胞 IFNα 产生。
