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Homeostatic Milieu Induces Production of Deoxyribonuclease 1–like 3 from Myeloid Cells
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-03-18 , DOI: 10.4049/jimmunol.1901304
Shoichiro Inokuchi , Hiroki Mitoma , Shotaro Kawano , Shota Nakano , Masahiro Ayano , Yasutaka Kimoto , Mitsuteru Akahoshi , Yojiro Arinobu , Hiroshi Tsukamoto , Koichi Akashi , Takahiko Horiuchi , Hiroaki Niiro

Key Points Myeloid cells are the dominant cell type expressing DNase1L3 in human blood cells. Homeostatic stimuli may be a key driver of DNase1L3 production in myeloid cells. DNase 1–like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4–induced DNase1L3 expression. IL-4–treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome–DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA.

中文翻译:

稳态环境诱导骨髓细胞产生脱氧核糖核酸酶 1 样 3

要点 骨髓细胞是人类血细胞中表达 DNase1L3 的主要细胞类型。稳态刺激可能是骨髓细胞中 DNase1L3 产生的关键驱动因素。DNase 1-like 3 (DNase1L3) 属于 DNase1 家族,最初被鉴定为一种与细胞凋亡和坏死相关的核酸内切酶,可将核小体内 DNA 片段化。在系统性红斑狼疮 (SLE) 的小鼠模型和家族性 SLE 患者中报告了功能丧失突变。这些报告表明 DNase1L3 在预防 SLE 发展中起着重要作用;然而,DNase1L3 在人类免疫系统中的表达和功能在很大程度上尚未阐明。正如之前的报道显示 DNase1L3 在造血器官中表达,我们首先通过定量实时 PCR 分析了每个人外周血细胞亚群中 DNase1L3 的表达水平。浆细胞样树突细胞在外周血细胞中显示出最高的 DNase1L3 mRNA 表达水平。IL-4 增强了单核细胞、单核细胞衍生的树突细胞和单核细胞衍生的巨噬细胞 (MDM) 中 DNase1L3 的表达,但在 T 细胞、B 细胞或浆细胞样树突细胞中不表达。与 IL-4、全反式视黄酸和凋亡细胞一起有效上调 MDM 中 DNalse1L3 的表达。作为细胞内信号分析的结果,Jak1-IRS2-ERK/PI3K 通路对于 IL-4 诱导的 DNase1L3 表达是必不可少的。IL-4 处理的单核细胞衍生的树突细胞和 MDM 分泌活性 DNase1L3 蛋白,可以降解对 DNase1 有抗性的脂质体-DNA 复合物。
更新日期:2020-03-18
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