PDF(Pubmed)
Abstract：
Recently, a major single nucleotide variant on the NCF1 gene, leading to an amino acid replacement from arginine to histidine at position 90 (NCF1R90H), associated with low production of reactive oxygen species (ROS), was found to be causative for several autoimmune diseases. Psoriasis in the skin (PsO) and psoriatic arthritis (PsA) were induced with mannan by intraperitoneal injection or epicutaneous application, evaluated by visual and histology scoring. Immunostaining was used to identify macrophages, NCF1, and keratinocytes. The population of immune cells was quantified by flow cytometry, gene expression was analyzed by RT-qPCR, and the JAK/STAT signaling pathway was investigated by immunohistochemical staining and western blot. We found that the low ROS responder NCF190H variant promotes PsO and PsA (the MIP model). The NCF190H-expressing mice had hyperactivated macrophages, expanded keratinocytes, and dramatically increased numbers of γδT17 cells with upregulated IL-17A, IL-23, and TNF-α. In addition, the JAK1/STAT3 signaling pathway was also upregulated in cells in the psoriatic skin tissues of Ncf190H mice. To summarize, a defined SNP (NCF1-339, also named NCF190H) was found to activate the IL-23/IL-17 axis and JAK-STAT signaling pathways, leading to hyperactivation of macrophages and keratinocytes and causing mouse psoriasis and psoriatic arthritis.
摘要：
最近,NCF1基因上的主要单核苷酸变异，导致氨基酸从精氨酸替换为位置90的组氨酸（NCF1R90H），与低产量的活性氧（ROS）相关，被发现是几种自身免疫性疾病的病因。通过腹膜内注射或表皮应用甘露聚糖诱导皮肤中的银屑病（PsO）和银屑病关节炎（PsA），通过视觉和组织学评分进行评估。免疫染色用于识别巨噬细胞，NCF1和角质形成细胞。通过流式细胞术对免疫细胞群进行定量,通过RT-qPCR分析基因表达，并通过免疫组织化学染色和蛋白质印迹研究JAK/STAT信号通路。我们发现低ROS应答者NCF190H变体促进PsO和PsA(MIP模型)。表达NCF190H的小鼠具有过度活化的巨噬细胞，扩增的角质形成细胞，IL-17A上调的γδT17细胞数量急剧增加，IL-23和TNF-α。此外,在Ncf190H小鼠的银屑病皮肤组织中,JAK1/STAT3信号通路也被上调.总结一下,一个定义的SNP（NCF1-339，也称为NCF190H）被发现激活IL-23/IL-17轴和JAK-STAT信号通路，导致巨噬细胞和角质形成细胞过度活化，并引起小鼠银屑病和银屑病关节炎。
