Functional analyses of leukocyte integrins and its regulatory molecule in glomerulonephritis and those application for cell transfer therapy

• Project/Area Number: 16K09611
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Fujita Health University (2018); Nagoya University (2016-2017)
• Principal Investigator: Tsuboi Naotake 藤田医科大学, 医学部, 准教授 (50566958)
• Co-Investigator(Kenkyū-buntansha): 丸山 彰一 名古屋大学, 医学系研究科, 教授 (10362253)
• Research Collaborator: ARASE Hisashi ; DU Qiuna ; SUGIYAMA Yutaka ; KITAGAWA Akimitsu ; KOBAYASHI Yoichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); 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: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 抗腎糸球体基底膜抗体型腎炎 / 白血球活性化 / 接着因子 / 好中球 / 免疫複合体 / 白血活性化 / マクロファージ / 多光子励起レーザー走査型顕微鏡 / アゴニスト / TLR / 接着因子抑制 / 免疫学 / 生体分子 / 病理学 / 細胞・組織

Outline of Final Research Achievements

【Background】PILRα expressed on leukocytes has regulatory functions in leukocyte β2 integrin activation during acute inflammation. Here, we investigated its roles in antibody-mediated glomerular inflammation.【Results】PILRα-/- mice with NTS-GN demonstrated severe glomerular injury. Enhanced glomerular neutrophil accumulation was observed in NTS-GN PILRα-/- only under pre-immunized conditions. PILRα-/- neutrophils exhibited enhanced spreading and adhesion to ICs compared to those in WT cells.【Conclusion】PILRα negatively regulates antibody-mediated neutrophil recruitment, leading to renal injury, by inhibiting Mac-1 integrin activation.

Academic Significance and Societal Importance of the Research Achievements

本研究から白血球発現分子PILRαの接着因子Mac-1制御を介する抗体型糸球体腎炎抑制効果が明らかとなった。またPILRαによる接着因子活性化抑制機能は炎症時にのみ発揮された。したがってPILRαの活性化は、抗体型糸球体腎炎のみならず、関節リウマチ、全身性エリテマトーデスなどの炎症性自己免疫疾患に対する有望な治療ターゲットとして考えられる。

Research Products

• [Journal Article] Urinary levels of the leukocyte surface molecule CD11b associate with glomerular inflammation in lupus nephritis. (2019)
  • Author(s): Kitagawa A, Tsuboi N, Yokoe Y, Katsuno T, Ikeuchi H, Kajiyama H, Endo N, Sawa Y, Suwa J, Sugiyama Y, Hachiya A, Mimura T, Hiromura K, Maruyama S.
  • Journal Title: Kidney Int. Volume: 95(3) Issue: 3 Pages: 680-692
  • DOI: 10.1016/j.kint.2018.10.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] リツキシマブの腎疾患治療への応用 (2018)
  • Author(s): 坪井直毅、勝野敬之、丸山彰一
  • Journal Title: 診断と治療 Volume: 106（4）
• [Journal Article] Transfusion of CD206+ M2 Macrophages Ameliorates Antibody-Mediated Glomerulonephritis in Mice. (2016)
  • Author(s): Du Q, Tsuboi N, Shi Y, Ito S, Sugiyama Y, Furuhashi K, Endo N, Kim H, Katsuno T, Akiyama S, Matsuo S, Isobe KI, Maruyama S.
  • Journal Title: Am J Pathol. Volume: 186 Issue: 12 Pages: 3176-3188
  • DOI: 10.1016/j.ajpath.2016.08.012
  • Peer Reviewed
• [Journal Article] Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis. (2016)
  • Author(s): Endo N, Tsuboi N, Furuhashi K, Shi Y, Du Q, Abe T, Hori M, Imaizumi T, Kim H, Katsuno T, Ozaki T, Kosugi T, Matsuo S, Maruyama S.
  • Journal Title: Nephrol Dial Transplant Volume: 31(12) Issue: 12 Pages: 2023-2033
  • DOI: 10.1093/ndt/gfw214
  • NAID: 120006220242
  • Peer Reviewed
• [Presentation] Urinary CD11b and CD163 Reflect Clinical and Histological Diseas Activity in Renal Involvement of Anti-Neutrophil Cytoplasmic Anti-body-Associated Vasculitides. (2018)
  • Author(s): Yuki Yokoe, Naotake Tsuboi, Shoichi Maruyama
  • Organizer: Kidney Week 2018 - San Diego, CA
  • Int'l Joint Research
• [Presentation] Urinary CD11B, an Alpha Submit Integrin MAC-1, Associates with Histological Disease Activity in Lupus Nephritis. (2018)
  • Author(s): Akimitsu Kitagawa, Naotake Tsuboi, Takayuki Katsuno, Shoichi Maruyama
  • Organizer: The 55th ERA-EDTA Congress
  • Int'l Joint Research
• [Presentation] Negative regulation of integrin Mac-1 by paired immunoglobulin-like type2 receptor a (PILRa) enhances immune complex-mediated glomerulonephritis (2018)
  • Author(s): Yutaka Sugiyama, Naotake Tsuboi, Yuko Shimamura, Akimitsu Kitagawa, Yutaka Kamimura, Shoichi Maruyama
  • Organizer: ISN Frontiers Meetings 2018
  • Int'l Joint Research
• [Presentation] PAIRED IMMUNOGLOBULIN-LIKE TYPE2 RECEPTOR ALPHA (PILRA) NEGATIVELY REGULATES MOUSE CRESCENTIC GLOMERULONEPHRITIS (2018)
  • Author(s): Yutaka Sugiyama。Naotake Tsuboi,Yuko Shimamura,Akimitsu Kitagawa, Yutaka Kamimura, Asuka HorinouchiTakayuki Katsuno,and Shoichi Maruyama
  • Organizer: the 18th international vasculitis & ANCA workshop
  • Int'l Joint Research
• [Presentation] PAIRED IMMUNOGLOBULIN-LIKE TYPE2 RECEPTOR ALPHA (PILRA) NEGATIVELY REGULATES MOUSE CRESCENTIC GLOMERULONEPHRITIS (2017)
  • Author(s): Yutaka Sugiyama。Naotake Tsuboi,Yuko Shimamura,Akimitsu Kitagawa, Yutaka Kamimura, Asuka HorinouchiTakayuki Katsuno,and Shoichi Maruyama
  • Organizer: the 18th international vasculitis & ANCA workshop
  • Place of Presentation: 東京大学（東京都文京区）
  • Year and Date: 2017-03-26
  • Int'l Joint Research
• [Presentation] 腎糸球体炎症とマクロファージ (2016)
  • Author(s): 坪井 直毅
  • Organizer: 第46回 日本腎臓学会西部学術大会
  • Place of Presentation: シーガイアコンベンションセンター（宮崎県宮崎市）
  • Year and Date: 2016-10-14
• [Presentation] Paired immunoglobulin-like type2 receptor α (PILRα) negatively regulates antibody-mediated glomerulonephritis. (2016)
  • Author(s): Yutaka Sugiyama, Naotake Tsuboi, Du Qiuna, Yutaka Kamimura, Shoichi Maruyama, Seiichi Matsuo.
  • Organizer: ISN Nexus 2016
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2016-04-17
  • Int'l Joint Research
• [Book] Basic nephrology「Alternatively activated macrophageと腎疾患」 (2016)
  • Author(s): 坪井直毅、丸山彰一
  • Total Pages: 206
  • Publisher: 中外医学社