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Role of transcription factor Fli-1 in chemokine expression and SLE pathogenesis for development of novel therapies

Research Project

Project/Area Number 20K08804
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54020:Connective tissue disease and allergy-related
Research InstitutionFukushima Medical University

Principal Investigator

Shuzo Sato  福島県立医科大学, 医学部, 准教授 (20535231)

Co-Investigator(Kenkyū-buntansha) 鬼澤 道夫  福島県立医科大学, 医学部, 助教 (30783352)
渡辺 浩志  福島県立医科大学, 医学部, 教授 (40336467)
右田 清志  福島県立医科大学, 医学部, 教授 (60264214)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsループス腎炎 / Fli-1 / ケモカイン / CXCL13 / ループスモデルマウス / SLE / 転写因子 / 全身性エリテマトーデス / サイトカイン / ループス様腎炎
Outline of Research at the Start

ループス腎炎は、全身性エリテマトーデス(SLE)に合併し、難治例の克服が課題となっている。SLEでは転写因子Fli-1の発現亢進が見られるが、その詳細は不明であった。近年申請者らはFli-1発現抑制によりループス様腎炎を著明に改善させること、及びFli-1が複数のサイトカイン、ケモカイン発現を直接制御しループス腎炎の病態に関与することを初めて見出した。今回、SLEと強く関連しているケモカインCXCL13に注目し、CXCL13におけるループス腎炎制御機構およびFli-1によるCXCL13の細胞内制御機構を明らかにする。最終的には、Fli-1制御によるSLE新規治療法開発の基盤を提供する。

Outline of Final Research Achievements

Previous reports have shown that transcription factor Fli-1 regulates cytokine/chemokine expression in lupus nephritis. This study aims to elucidate association between Fli-1 and CXCL13 expression, a chemokine which attracts B cells and promotes ectopic lymphoid structures (TLS). Adult Fli-1+/- (heterozygote) MRL/lpr mice showed reduced serum CXCL13 levels and reduced mRNA expression of CXCL13 and Sox4 in the kidney compared to wild-type (WT) littermates. The CXCL13-positive and CXCR5-positive immune cells were also reduced in Fli-1+/- mice. Immunofluorescence microscopy showed reduced CXCL13/CD11b double positive cells, indicates reduced CXCL13 positive monocytes infiltration in TLS lesion of the kidney. Taken together, Fli-1 affects CXCL13 and Sox4 expression in the kidney, which may influence the severity of lupus-like nephritis in MRL/lpr mice. Fli-1 inhibition could be a novel target for treating lupus nephritis and SLE.

Academic Significance and Societal Importance of the Research Achievements

ループス腎炎は全身性エリテマトーデス(SLE) に合併する最も頻度の高い臓器病変であり、SLEの予後を左右する重要な因子であるにも関わらず、未だ難治例の克服が問題となっている。転写因子Fli-1はサイトカイン、ケモカイン発現制御によってループス腎炎における炎症に関与しており、今回の研究でFli-1がCXCL13やSox4発現にも重要な役割を果たすことが判明した。Fli-1をはじめとした転写因子を制御することにより、すなわちドラッグリポジショニングや新規薬剤などの開発によりSLE治療へのさらなる貢献が期待できる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (3 results)

All 2023 2022 2020

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Transcription factor Fli-1 impacts the expression of CXCL13 and regulates immune cell infiltration into the kidney in MRL/lpr mouse2023

    • Author(s)
      Sato Shuzo、Zhang Xian K、Matsuoka Naoki、Sumichika Yuya、Saito Kenji、Yoshida Shuhei、Matsumoto Haruki、Temmoku Jumpei、Fujita Yuya、Asano Tomoyuki、Migita Kiyoshi
    • Journal Title

      Lupus Science & Medicine

      Volume: 10 Issue: 1 Pages: e000870-e000870

    • DOI

      10.1136/lupus-2022-000870

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] -2020

    • Author(s)
      -
    • Journal Title

      -

      Volume: -

    • Related Report
      2020 Research-status Report
  • [Presentation] Transcription Factor Fli-1 Impacts CXCL13 Expression and Renal Inflammation in Lupus-like Nephritis of Adult MRL/lpr Mouse2022

    • Author(s)
      Shuzo Sato
    • Organizer
      ACR convergence 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

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