The pathogenesis of S1PR1 reduction via miR223-3p in Lupus T cells.

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17442
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Sumie Asano 川崎医科大学, 医学部, 講師 (80816497)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: SLE / S1PR1 / microRNA / エピジェネティクス

Outline of Final Research Achievements

The micro RNAs (miRNAs) and their target mRNAs in CD4+ cells in systemic lupus erythematosus patients were suggested to play a key role in the pathogenesis. To identify new miRNAs related genes, we integrated mRNA and miRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified downregulation of sphingosine-1-phosphate receptor 1 (S1pr1) and upregulation of Mir223 in MRL compared with B6 mice.We generated the B6-Mir223-/-Faslpr/lpr mice and the lupus phenotypes were analyzed. In B6-Mir223-/-Faslpr/lpr mice, S1PR1+CD4+ T cells in the spleen was significantly increased compared with that in B6-Mir223+/+Faslpr/lpr mice by flow cytometry. B6-Mir223-/-Faslpr/lpr mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1+CD4+ T cells.
The deletion of Mir223 exacerbated the lupus phenotypes.

Free Research Field

リウマチ膠原病学

Academic Significance and Societal Importance of the Research Achievements

SLEの新規治療薬を見いだすため、その発症機序に着目し、後天的遺伝子制御に関与するmiRNAとそのターゲットmRNAを探索した。SLEのCD4陽性T細胞で、miR223の発現を代償的に亢進させることにより標的遺伝子であるスフィンゴシン1-リン酸受容体 (S1pr1)の発現を低下させ、脾臓CD4陽性T細胞の増加とその糸球体への浸潤を抑制し、尿蛋白および糸球体スコアの増悪を抑制していることを確認した。ループス腎炎においてMir223の発現亢進は代償的にループス腎炎悪化を抑制する役割を果たすことが示唆された。Mir223 がSLEの病態解明や新規治療ターゲットになりうることが期待される。