Immunological analysis of glucose intolerance induced by hyperactivated dendritic cells

• Project/Area Number: 19K08902
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Gunma University
• Principal Investigator: KANEKO YORIAKI 群馬大学, 医学部附属病院, 講師 (00334095)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 樹状細胞 / ホスファターゼ / Shp-1 / 2型糖尿病 / Shp1 / 自己免疫疾患

Outline of Research at the Start

樹状細胞はT細胞の活性化や自然免疫応答に重要な細胞である。樹状細胞の機能解析を目的として、樹状細胞特異的にチロシン脱リン酸化酵素Shp-1を欠損する遺伝子改変マウスShp-1 CKOを作成した。Shp-1 CKOは樹状細胞が活性化し、高齢になると自己免疫疾患を発症する。本研究課題では、Shp-1 CKOに高脂肪食を給餌して、ヒトの2型糖尿病のマウスモデルを作成する。肥満に伴う耐糖能障害においては、免疫細胞の機能障害が報告されているので、Shp-1 CKOにみられる内分泌代謝の変化を免疫異常の観点から解析する。本研究を遂行することで、2型糖尿病における樹状細胞やT細胞などの関与が明らかになる。

Outline of Final Research Achievements

Abnormalities of the immune system are associated with the development of type 2 diabetes (T2D). In this project, we tried to analyze the contribution of a cytoplasmic tyrosine phosphatase Shp-1 expressed on dendritic cells (DC) in the pathogenesis of T2D. Shp-1 CKO the conditional knockout mice, which lack Shp-1 specifically in DC, had a mild degree of glucose intolerance and had mild data abnormalities related to glycolipid metabolism when they were subjected to a high-fat diet (HFD). Increased production of IL-10, an anti-inflammatory cytokine, and increased sugar consumption in the spleen are considered as possible mechanisms for the resistance of Shp-1 CKO to HFD-induced glucose intolerance.

Academic Significance and Societal Importance of the Research Achievements

CD11cを発現するDCやマクロファージにおいてShp-1を欠損させると、高脂肪食を負荷しても耐糖能の悪化が少ないことがコンディショナルノックアウトマウスの解析から明らかになった。今回の解析を通じて、CD11cを発現する細胞のShp-1を標的とした治療法が直ちに開発できる可能性は少ないと思われたが、IL-10をターゲットにする治療法の開発を探索するなど、本研究課題を通じてT2Dの病態解明や治療法の開発における端緒が得られた。

Research Products

• [Journal Article] Importance of methodology in the evaluation of renal mononuclear phagocytes and analysis of a model of experimental nephritis with Shp1 conditional knockout mice (2020)
  • Author(s): Watanabe Mitsuharu、Kaneko Yoriaki、Ohishi Yuko、Kinoshita Masato、Sakairi Toru、Ikeuchi Hidekazu、Maeshima Akito、Saito Yasuyuki、Ohnishi Hiroshi、Nojima Yoshihisa、Matozaki Takashi、Hiromura Keiju
  • Journal Title: Biochemistry and Biophysics Reports Volume: 22 Pages: 100741-100741
  • DOI: 10.1016/j.bbrep.2020.100741
  • Peer Reviewed / Open Access
• [Presentation] CD11c-dependent ablation of the protein tyrosine phosphatase Shp1 improves insulin resistance (2021)
  • Author(s): Shreya Shrestha, Yoriaki Kaneko, Masato Kinoshita, Yoichi Imai, Junya Suwa, Mitsuharu Watanabe, Yuko Ohishi, Yasuyuki Saito, Hiroshi Ohnishi, Takashi Matozaki, Keiju Hiromura
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] CD11C-SPECIFIC ABLATION OF SHP1 INDUCES AUTOIMMUNE SIALADENITIS SIMILAR TO SJOGREN'S SYNDROME (2020)
  • Author(s): M. Kinoshita, Y. Kaneko, M. Watanabe, Y. Imai, S. Shrestha, J. Suwa, Y. Ohishi, H. Hamatani, M. Nakasatomi, T. Sakairi, H. Ikeuchi, Y. Nojima, K. Hiromura.
  • Organizer: Annual European Congress of Rheumatology
  • Int'l Joint Research
• [Presentation] 腎虚血再灌流によりMSR1を高発現したマクロファーシが増加する (2020)
  • Author(s): 諏訪絢也, 金子和光, 渡辺光治, 今井陽一, Shrestha Shreya, 木下雅人, 大石裕子, 中里見征央, 浜谷博子, 坂入徹, 池内秀和, 廣村桂 樹
  • Organizer: 第63回日本腎臓学会学術総会
• [Presentation] Specific depletion of Shp1 in CD11c+ cells improves glucose intolerance in high fat diet-induced obesity (2019)
  • Author(s): Shreya Shrestha, Yoriaki Kaneko, Mitsuharu Watanabe, Masato Kinoshita, Yoichi Imai, Junya Suwa, Yuko Ohishi, Yasuyuki Saito, Hiroshi Ohnishi, Takashi Matozaki, Keiju Hiromura
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Establishment of a Preparative Method and Gating Strategy for Renal Mononuclear Phagocytes (rMophs) and Analysis of rMophs in CD11c-Specifc Shp-1 Knockout Mice (2019)
  • Author(s): Watanabe Mitsuharu, Kaneko Yoriaki, Kinoshita Masato, Shrestha Shreya, Ohishi Yuko, Sakairi Toru, Ikeuchi Hidekazu, Nojima Yoshihisa, Hiromura Keiju
  • Organizer: Kidney Week, American Society of Nephrology
  • Int'l Joint Research