Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan.
Front Immunol. 2021 Jan 26;11:616141. doi: 10.3389/fimmu.2020.616141. eCollection 2020.
The micro RNAs (miRNAs) and their target mRNAs are differentially expressed in various immune-mediated cells. Here, we investigated the role of and sphingosine-1-phosphate receptor 1 () in the pathogenesis of systemic lupus erythematosus.
We analyzed miRNA and mRNA profiling data of CD4 splenic T cells derived from MRL/MpJ- /J mice. We performed 3' untranslated region (UTR) luciferase reporter gene assay using human umbilical vein endothelial cells (HUVECs). We generated the B6- mice and the lupus phenotypes were analyzed.
In CD4 splenic T cells, we identified upregulation of miR-223-3p and downregulation of the possible target, by RNA sequencing of MRL/MpJ- /J mice. The transfection with miR-223-3p mimic significantly suppressed a luciferase activity in HUVEC treated with a Lentivirus vector containing 3' UTR of . The mRNA levels of were significantly decreased after miR-223-3p overexpression. In B6- mice, the proportion of CD3 T cells, CD3CD4CD8 cells, B cells, plasma cells, and S1PR1CD4 T cells in the spleen was significantly increased compared with that in B6- mice by flow cytometry. B6- mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1CD4 T cells.
Unexpectedly, the deletion of exacerbated the lupus phenotypes associated with increased population of S1PR1CD4 T in spleen and the enhanced infiltration of S1PR1CD4 T cells in inflamed kidney tissues, suggesting compensatory role of in the pathogenesis of lupus nephritis.
微小 RNA（miRNA）及其靶信使 RNA（mRNA）在各种免疫介导的细胞中差异表达。在此，我们研究了 miRNA 和鞘氨醇-1-磷酸受体 1（S1PR1）在系统性红斑狼疮发病机制中的作用。
我们分析了来自 MRL/MpJ-/-J 小鼠的 CD4 脾 T 细胞的 miRNA 和 mRNA 谱数据。我们使用人脐静脉内皮细胞（HUVEC）进行 3'非翻译区（UTR）荧光素酶报告基因检测。我们生成了 B6-/-小鼠，并分析了狼疮表型。
在 CD4 脾 T 细胞中，我们通过 MRL/MpJ-/-J 小鼠的 RNA 测序鉴定到 miR-223-3p 的上调和可能靶基因的下调。转染 miR-223-3p 模拟物可显著抑制含有 S1PR1 3'UTR 的慢病毒载体处理的 HUVEC 中的荧光素酶活性。miR-223-3p 过表达后，的 mRNA 水平显著降低。与 B6-/-小鼠相比，B6-/-小鼠的脾中 CD3 T 细胞、CD3CD4CD8 细胞、B 细胞、浆细胞和 S1PR1CD4 T 细胞的比例通过流式细胞术显著增加。B6-/-小鼠的肾小球和肾血管评分升高，与肾小球内 S1PR1CD4 T 细胞浸润增强相关。
出乎意料的是，缺失 S1PR1 加剧了狼疮表型，与脾中 S1PR1CD4 T 细胞数量增加以及炎症肾组织中 S1PR1CD4 T 细胞浸润增强有关，这表明 S1PR1 在狼疮肾炎发病机制中具有代偿作用。
