The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus.
The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus.
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DOI：
10.1002/jlb.3ab0518-180rr
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发表时间：
2019-10
影响因子：
5.5
通讯作者：
Gallucci S
中科院分区：
文献类型：
--
作者：
Lee MH;Gallo PM;Hooper KM;Corradetti C;Ganea D;Caricchio R;Gallucci S
白细胞介素（IL）-10在自身免疫性疾病系统性红斑狼疮（SLE）中升高。在这里，我们表明，传统的树突状细胞（cDCs）从疾病前狼疮倾向B6.NZM Sle 1/Sle 2/Sle 3三重同源（TCSle）小鼠产生更多的IL-10比野生型同源cDCs TLR刺激后，这种过度生产是通过阻断I型IFN受体（IFNAR）的特异性抗体。用I型IFN引发野生型cDC模拟TCSle cDC的IL-10过度产生。MAP激酶ERK在狼疮cDC中更磷酸化，部分促成IL-10过度产生。此外，我们发现TCSle cDC在TLR 7/TLR 9刺激后表达更高水平的IL-27，并且IFNAR阻断降低了TCSle cDC中的IL-27水平。这些结果表明，cDC中I型IFN的失调有助于SLE中IL-10和IL-27的增加。由于IL-27中和不抑制TLR诱导的IL-10产生，我们提出I型IFN独立于IL-27增强TCSle cDC中的IL-10。此外，SLE患者队列的RNA测序分析揭示了在表达高IFN特征的SLE患者中这些细胞因子的较高基因表达。由于IL-27和IL-10具有促炎和抗炎作用，我们的研究结果还表明，这些细胞因子可以通过SLE患者试验中的治疗性IFN阻断来调节，并且对自身免疫反应具有复杂的影响。在鼠狼疮cDC中增强的I型IFN-IL-27 / IL-10分子网络的模型。鼠狼疮cDC由于提高的自分泌I-IFN信号而过度产生IL-10和IL-27。此外，SLE患者中升高的IL-10和IL-27与高IFN Signature相关。
Interleukin (IL)-10 is elevated in the autoimmune disease systemic lupus erythematosus (SLE). Here we show that conventional dendritic cells (cDCs) from pre-disease lupus-prone B6.NZM Sle1/Sle2/Sle3 triple congenic (TCSle) mice produce more IL-10 than wild type congenic cDCs upon TLR stimulation, and this overproduction is prevented by blocking the type I IFN receptor (IFNAR) with specific antibodies. Priming wild type cDCs with type I IFN mimics the IL-10 overproduction of TCSle cDCs. The MAP kinase ERK is more phosphorylated in lupus cDCs, partially contributing to IL-10 overproduction. Moreover, we found that TCSle cDCs express higher levels of IL-27 upon TLR7/TLR9 stimulation, and IFNAR blockade reduced IL-27 levels in TCSle cDCs. These results suggest that dysregulated type I IFNs in cDCs contribute to the increased IL-10 and IL-27 in SLE. Since IL-27 neutralization did not inhibit TLR-induced IL-10 production, we propose that type I IFNs enhanced IL-10 in TCSle cDCs independently from IL-27. Moreover, RNA sequencing analysis of a cohort of SLE patients reveals higher gene expression of these cytokines in SLE patients expressing a high IFN signature. Since IL-27 and IL-10 have both pro- and anti-inflammatory effects, our results also suggest that these cytokines can be modulated by the therapeutic IFN blockade in trials in SLE patients and have complex effects on the autoimmune response. Model of a type I IFN - IL-27 / IL-10 molecular network augmented in murine lupus cDCs. Murine lupus cDCs overproduce IL-10 and IL-27 due to heightened autocrine I-IFN Signature. Furthermore, elevated IL-10 and IL-27 correlate with high IFN Signature in SLE patients.