Pathological involvement of RAGE/HMGB1 Axis in systemic lupus erythematosus

• Project/Area Number: 16K19600
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Okayama University
• Principal Investigator: Watanabe Haruki 岡山大学, 大学病院, 助教 (10761132)
• Research Collaborator: WATANABE katsue ; SADA ken-ei ; YAMAMOTO hiroshi ; WADA jun
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: SLE / RAGE / プリスタン / 全身性エリテマトーデス / 肺血管炎 / 免疫学

Outline of Final Research Achievements

Intraperitoneal administration of pristane causes inflammation and symptoms similar to systemic lupus erythematosus (SLE) such as nephritis and arthritis. When pristane is administered to RAGE deficient C57BL/6 mice, the survival rate tends to be improved as compared to wild-type mice. Resident macrophages seem to ameliorate the alveolar hemorrhage and rescue the survivors. Furthermore, deletion of the RAGE gene in MRL/lpr mice, another spontaneous SLE model, reduced proteinuria and decreased the weight of spleen and lymph nodes. These results indicate that RAGE plays a role in promoting disease in SLE and may be a potential therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

これまでRAGEのSLEにおける役割については相反する報告があり結論が出ていなかった。RAGEの働きを抑えるsRAGEという物質を、SLEモデルマウスに投与するとSLEが改善したという報告がある一方、別のSLEモデルマウスのRAGE遺伝子を欠失させるとSLEが悪化したという報告がなされていた。後者の報告では軽症のSLEを発症するモデルマウスが使用されており、本研究による2つのモデルマウスの検討から、より強い炎症状態にある重篤な病態においてはRAGEはSLEの有望な治療標的となる可能性が示された。

Research Products

• [Journal Article] Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice. (2017)
  • Author(s): Watanabe H, Watanabe KS, Liu K, Hiramatsu S, Zeggar S, Katsuyama E, Tatebe N, Akahoshi A, Takenaka F, Hanada T, Akehi M, Sasaki T, Sada KE, Matsuura E, Nishibori M, Wada J.
  • Journal Title: Molecular Therapy - Methods & Clinical Development Volume: 6 Pages: 31-39
  • DOI: 10.1016/j.omtm.2017.05.006
  • Peer Reviewed / Open Access
• [Presentation] SLEモデルマウスにおける最終糖化産物受容体（receptor for advanced glycation endproducts : RAGE）の果たす役割 (2019)
  • Author(s): 渡辺晴樹
  • Organizer: 日本臨床免疫学会 Midwinter Seminar 2019