The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells
The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells
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DOI：
10.1186/s13075-020-02186-z
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发表时间：
2020-06-05
影响因子：
4.9
通讯作者：
Ronnblom, Lars
中科院分区：
文献类型：
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作者：
Hjorton, Karin;Hagberg, Niklas;Ronnblom, Lars
目的：系统性红斑狼疮（SLE）患者由于浆细胞样树突状细胞（pDCs）的激活而持续产生干扰素（IFN），可通过含有免疫复合物（RNA- ic）的RNA触发I型IFN合成。考虑到新出现的数据表明III型IFN在SLE疾病过程中的作用，我们询问RNA-IC是否可以诱导pDC中III型IFN的产生以及如何调节这种产生。方法：从健康献血者或SLE患者中分离外周血单个核细胞（PBMCs）或免疫细胞亚群，用含有U1 snRNP和SLE- igg （RNA-IC）的IC刺激。在细胞培养中加入羟氯喹（HCQ）和白细胞介素受体1相关激酶4抑制剂（IRAK4i）。细胞因子mRNA水平用芯片检测，蛋白水平用免疫分析法检测。采用ddSEQ技术对pDCs进行单细胞RNA测序。结果：在rna - ic刺激的pDC-NK和pDC-B细胞共培养中诱导了III型IFN mRNA和蛋白。激活的pDCs子集（3%）同时表达III型和I型IFN mRNA。IFN-lambda 2、ifn - α 2b、白细胞介素(IL)-3、IL-6或粒细胞-巨噬细胞集落刺激因子（GM-CSF）可使IFN-lambda 1/3的生成增加2-5倍。HCQ和IRAK4i阻断了rna - ic触发的IFN-lambda 1/3的产生(p
Objective: Patients with systemic lupus erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III IFN in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC and how this production can be regulated.Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1-associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA sequencing of pDCs using ddSEQ technology was performed.Results: Type III IFN mRNA and protein was induced in RNA-IC-stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-lambda 2, IFN-alpha 2b, interleukin (IL)-3, IL-6, or granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced IFN-lambda 1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-lambda 1/3 production (p