Le Ethan, Moadab Fatemeh, Wang Xiaoxing, Najjar Rayan, Van den Bogaerde Sadie J, Bays Alison, LaCava John, Mustelin Tomas
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, USA.
Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, New York, USA.
Eur J Immunol. 2025 Mar;55(3):e2451351. doi: 10.1002/eji.202451351.
Approximately 17% of our genome consists of copies of the retrotransposon "long interspersed element-1" (LINE-1 or L1). Patients with systemic lupus erythematosus (SLE) frequently have autoantibodies against the L1-encoded ORF1 protein (ORF1p), which correlate with disease activity and interferon gene signature. ORF1p is present in neutrophils from patients with active disease in perinuclear ribonucleoprotein particles that also contain Ro60 and nucleic acid sensors. Here, we report that treatment of neutrophils or monocytes with the demethylating agent 5-aza-deoxycytidine, interferon-α, tumor necrosis factor-α, and other cytokines or toll-like receptor agonists, induce a rapid increase in L1 transcripts. This increase was greater in cells from patients with SLE or rheumatoid arthritis (RA) than in cells from healthy donors, except that cells from SLE did not respond to interferon-α, presumably because most SLE patients have elevated type I interferons in vivo. Interferon-α also induced ORF1p in RA neutrophils with a subcellular distribution like that of ORF1p in freshly isolated SLE neutrophils. A luciferase reporter gene driven by the 5' untranslated region of L1, which controls its transcription, was also stimulated by interferon-α. These new insights into L1 transcriptional regulation indicate that it may play a more active role in antiviral immune responses.
我们的基因组中约17%由逆转录转座子“长散在核元件-1”（LINE-1或L1）的拷贝组成。系统性红斑狼疮（SLE）患者经常产生针对L1编码的ORF1蛋白（ORF1p）的自身抗体，这些抗体与疾病活动和干扰素基因特征相关。在患有活动性疾病的患者的中性粒细胞中，ORF1p存在于核周核糖核蛋白颗粒中，这些颗粒还含有Ro60和核酸传感器。在此，我们报告，用去甲基化剂5-氮杂-脱氧胞苷、干扰素-α、肿瘤坏死因子-α以及其他细胞因子或Toll样受体激动剂处理中性粒细胞或单核细胞，会导致L1转录本迅速增加。这种增加在SLE或类风湿关节炎（RA）患者的细胞中比在健康供体的细胞中更大，只是SLE患者的细胞对干扰素-α无反应，推测是因为大多数SLE患者体内I型干扰素水平升高。干扰素-α还在RA中性粒细胞中诱导出ORF1p，其亚细胞分布与新鲜分离的SLE中性粒细胞中的ORF1p相似。由控制L1转录的5'非翻译区驱动的荧光素酶报告基因也受到干扰素-α的刺激。这些对L1转录调控的新见解表明，它可能在抗病毒免疫反应中发挥更积极的作用。
