Roles for CD157 in functions of macrophage lineage cells and early pathophysiology of a rheumatoid arthritis model

• Project/Area Number: 17K08798
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kawasaki Medical School
• Principal Investigator: Ishihara Katsuhiko 川崎医科大学, 医学部, 教授 (10263245)
• Co-Investigator(Kenkyū-buntansha): 矢作 綾野 川崎医科大学, 医学部, 助教 (10584873) ; 井関 將典 川崎医科大学, 医学部, 講師 (30532353)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 結核 / 単球・マクロファージ / Toll様受容体2 / 活性酸素 / 関節リウマチ / IL-6/gp130/STAT3 / 滑膜細胞 / 線維化 / preclinical phase / 滑膜炎 / マクロファージ / 末梢血単球亜集団 / IL-6/gp130 / 血管新生 / 可溶性BST-1 / ROS産生 / TLR2 / Bst1-flox / gp130 / 骨髄系細胞特異的BST-1欠損 / BST-1 / CD157 / gp130F759 / マクロファージ様滑膜細胞 / 単球・マクロファージ亜集団 / CX3CR1 / CD157レポーターマウス / ADPリボシルシクラーゼ / BST-1/CD157 / CD38 / 関節リウマチモデル / 滑膜

Outline of Final Research Achievements

Collaboration study with Dr. Chen, who discovered increases of BST-1/CD157 in the sera and lung granuloma of the patients with tuberculosis, revealed increased susceptibility to Mycobacterium (M.) tuberculosis in Bst1-knockout mice(Bst1KO), and impaired signal transduction from TLR2/PKC zeta to production of reactive oxygen spices by macrophages lacking BST-1. In the early phase of arthritis in gp130F759, a murine model for rheumatoid arthritis, CX3CR1+ macrophage-like synoviocytes increased in the synovium and a CX3CR1+ monocyte subset decreased in the peripheral blood, indicating that local inflammation is reflected in the changes of subsets in peripheral blood. Lack of BST-1 ameliorated fibrosis in the synovium of gp130F759. We clarified physiological roles for BST-1 on macrophages in defense against M. tuberculosis and pathological roles of BST-1 promoting fibrosis in arthritis like rheumatoid arthritis.

Academic Significance and Societal Importance of the Research Achievements

BST-1(Bone marrow stromal cell antigen-1)/ CD157は関節リウマチ由来骨髄間質細胞に高発現するGPIアンカー型細胞膜外酵素(ADPリボシルシクラーゼ)であり、腸管-神経-免疫系の機能を制御する多機能分子である。ヒトとマウスで共通してBST-1を表面発現する細胞である単球・マクロファージ系に注目して、生体レベルでBST-1の機能解析を進めた結果、世界的に重要な感染症である結核に対する感染抵抗性促進機能、頻度の高い自己免疫疾患である関節リウマチのマウスモデルにおける線維化促進機能を明らかにしたことは、両疾患の治療法開発に有用な基盤的知見を提供する。

Research Products

• [Int'l Joint Research] Buck Institute(米国)
• [Int'l Joint Research] Shenzhen University School of Medicine/Shanghai Jiao Tong University/CAMS and Peking Union Med College(中国)
• [Int'l Joint Research] University of Leicester(英国)
• [Int'l Joint Research] Virginia Univ./Trudeau Institute(米国)
• [Int'l Joint Research] Shenzhen-HongKong Institute(中国)
• [Int'l Joint Research] ヴァージニア大学(米国)
• [Journal Article] Distinct physical condition and social behavior phenotypes of CD157 and CD38 knockout mice during aging. (2020)
  • Author(s): 2.Maria Gerasimenko; Olga Lopatina; Anna A. Shabalova; Stanislav M. Cherepanov; Alla B. Salmina; Shigeru Yokoyama; Hisanori Goto; Hiroshi Okamoto; Yasuhiko Yamamoto; Katsuhiko Ishihara; Haruhiro Higashida.
  • Journal Title: PLoS One Volume: 15(12) Issue: 8 Pages: 4169-4169
  • DOI: 10.3390/ijms22084169
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. (2020)
  • Author(s): Covarrubias AJ, Kale A, Perrone R, Lopez-Dominguez JA, Pisco AO, Kasler HG, Schmidt MS, Heckenbach I, Kwok R, Wiley CD, Wong HS, Gibbs E, Iyer SS, Basisty N, Wu Q, Kim IJ, Silva E, Vitangcol K, Shin KO, Lee YM, Riley R, Ben-Sahra I, Ott M, Ishihara K, Quake SR, Newman J, Brenner C, Campisi J, Verdin E. et al
  • Journal Title: Nat Metab Volume: 2 Issue: 11 Pages: 1265-1283
  • DOI: 10.1038/s42255-020-00305-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD157 Confers Host Resistance to Mycobacterium tuberculosis via TLR2-CD157-PKCzeta-Induced Reactive Oxygen Species Production (2019)
  • Author(s): Yang Qianting、Liao Mingfeng、Wang Wenfei、Zhang Mingxia、Chen Qi、Guo Jiubiao、Peng Bin、Huang Jian、Liu Haiying、Yahagi Ayano、Xu Xingzhi、Ishihara Katsuhiko、Cooper Andrea、Chen Xinchun、Cai Yi
  • Journal Title: mBio Volume: 10 Issue: 4
  • DOI: 10.1128/mbio.01949-19
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis (2019)
  • Author(s): Yahagi Ayano、Saika Taro、Hirano Hiroyasu、Takai-Imamura Miwa、Tsuji Fumio、Aono Hiroyuki、Iseki Masanori、Morita Yoshitaka、Igarashi Hideya、Saeki Yukihiko、Ishihara Katsuhiko
  • Journal Title: RMD Open Volume: 5 Issue: 2 Pages: e000853-e000853
  • DOI: 10.1136/rmdopen-2018-000853
  • Peer Reviewed / Open Access
• [Journal Article] CD157 Marks Tissue-Resident Endothelial Stem Cells with Homeostatic and Regenerative Properties. (2018)
  • Author(s): Wakabayashi T, Naito H, Suehiro JI, Lin Y, Kawaji H, Iba T, Kouno T, Ishikawa-Kato S, Furuno M, Takara K, Muramatsu F, Weizhen J, Kidoya H, Ishihara K, Hayashizaki Y, Nishida K, Yoder MC, Takakura N.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 3 Pages: 348-397
  • DOI: 10.1016/j.stem.2018.01.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson’s Disease (2017)
  • Author(s): Kasai, S., Yoshiara, T., Lopatina, O., Ishihara, K. and Higashida, H.
  • Journal Title: Frontiers in Behavioral Neuroscience Volume: 印刷中
  • DOI: 10.3389/fnbeh.2017.00075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Communication impairment in ultrasonic vocal repertoire during the suckling period of Cd157 knockout mice: transient improvement by oxytocin, (2017)
  • Author(s): Olga Lopatina, Kazumi Furuhara, Katsuhiko Ishihara, Alla B. Salmina, Haruhiro Higashida.
  • Journal Title: Front. Neurosci. Volume: -
  • DOI: 10.3389/fnins.2017.00266
  • NAID: 120006343974
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Lack of bone marrow stromal cell antigen-1 (BST-1)/CD157 ameliorated colitis induced by dextran sodium sulfate (DSS) (2021)
  • Author(s): Katsuhiko Ishihara , Ayano Yahagi , Masanori Iseki , Ryo Katsumata , Akiko Shiotani
  • Organizer: Virtual Immunology 2021
  • Int'l Joint Research
• [Presentation] 関節リウマチモデルgp130F759の最初期滑膜細胞におけるシングルセルRNA-seq解析 (2021)
  • Author(s): 矢作 綾野、井関 將典、石原 克彦
  • Organizer: 第65回日本リウマチ学会総会・学術集会
• [Presentation] BST-1/CD157の欠損による滑膜線維芽細胞のIL-6産生低下により、GP130F759の関節炎における線維化が軽減した。 (2020)
  • Author(s): 石原 克彦, 矢作 綾野, 井関 將典
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] BST-1/CD157はDSS誘発性大腸炎における腸上皮の傷害を促進させる (2020)
  • Author(s): 矢作 綾野、井関 將典、石原 克彦
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] 関節リウマチモデルgp130F759の最初期病変におけるIL-6-PAD4連関 -滑膜線維芽細胞と好中球の相互作用- (2020)
  • Author(s): 矢作 綾野、井関 將典、石原 克彦
  • Organizer: 第64回日本リウマチ学会総会・学術集会
• [Presentation] CX3CR1-eGFP+macrophage-like synoviocytes in gp130F759, a mouse model for rheumatoid arthritis (2019)
  • Author(s): Ayano Yahagi, Yujiro Yokoyama, Noritaka Tsunematsu, Masanori Iseki, Katsuhiko Ishihara.
  • Organizer: The 26th International Symposium on Molecular Cell Biology of Macrophages
  • Int'l Joint Research
• [Presentation] Toll-like receptor-induced Ab production from marginal zone B cells is negatively regulated by ADP-ribosyl cyclase BST-1/CD157 (2019)
  • Author(s): Masanori Iseki, Ayano Yahagi, Katsuhiko Ishihara
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research
• [Presentation] IL-6-PAD4 axis: IL-6 dependent PAD4 production in neutrophils at the earliest phase of arthritis in gp130F759. (2019)
  • Author(s): Ayano Yahagi, Taro Saika, Masanori Iseki, Katsuhiko Ishihara
  • Organizer: The 48th Annual Meeting of the Japanese for Immunology
  • Int'l Joint Research
• [Presentation] A novel function of ADP-ribosyl cyclases to regulate the length of the small intestine revealed in CD38/CD157 double knockout mice. (2018)
  • Author(s): Katsuhiko Ishihara, Ayano Yahagi, Masanori Iseki
  • Organizer: IMMUNOLOGY 2018, 2018.5.4-8, Austin,Texas
  • Int'l Joint Research
• [Presentation] Elongation of the small intestine and enlargement of the mesenteric lymph nodes in Bst1Cd38 double knockout mice. (2018)
  • Author(s): Katsuhiko Ishihara, Ayano Yahagi, Masanori Iseki
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology, Fukuoka
  • Int'l Joint Research
• [Presentation] Deletion of padi4 exacerbated the arthritis in gp130F759. (2018)
  • Author(s): Ayano Yahagi, Masanori Iseki, Kazuhiko Yamamoto, Katsuhiko Ishihara
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology, Fukuoka
  • Int'l Joint Research
• [Presentation] BST-1/CD157 negatively regulates marginal zone B cell survival and Ab production induced with Toll-like receptor stimulation (2018)
  • Author(s): Masanori Iseki, Ayano Yahagi, Katsuhiko Ishihara
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology, Fukuoka
  • Int'l Joint Research
• [Presentation] Bone Marrow Stromal Cell Antigen-1 Identified by RNA-Seq and ChIP-Seq Is important for Inducing Renal Ischemia-Reperfusion Injury and Fibrosis (2017)
  • Author(s): Inoue Tsuyoshi, Huang Liping, Rosin Diane L.,Ishihara Katsuhiko, Wada Youichiro, Okusa Mark D.
  • Organizer: Kidney week 2017
  • Int'l Joint Research
• [Presentation] BST-1/CD157 on B cells negatively regulates Toll-like receptor signaling (2017)
  • Author(s): Masanori Iseki, Ayano Yahagi, Katsuhiko Ishihara
  • Organizer: 第46回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] 関節リウマチモデルgp130F759の初期病態において関節のPadi4遺伝子が増強する (2017)
  • Author(s): 矢作 綾野, 石原 克彦
  • Organizer: 第28回 日本生体防御学会学術総会
• [Remarks] 川崎医科大学 免疫学教室
  • URL: https://m.kawasaki-m.ac.jp/classroom/course.php?id=208