Study on molecules that negatively regulate ROS production in human granulocyes

• Project/Area Number: 23659518
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MORIO Tomohiro 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (30239628)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 顆粒球 / 活性酸素(ROS) / シグナル伝達 / リン酸化 / Btk / Mal

Research Abstract

We studied the roles of Btk and Btk-associated molecules in regulation of reactive oxygen species (ROS) production. The enzyme responsible for the respiratory burst is NADPH oxidase. In the absence of Btk, the adaptor Mal was associated with PI(3)K and PTKs at the plasma membrane, whereas in control resting neutrophils, Btk interacted with and confined Mal in the cytoplasm. These kinases were hyper-phosphorylated and were activated. We delved into the mechanism of PTK activation in the absence of Btk by looking into the negative regulator of PTKs (e.g. Csk/Cbp and phosphatases). We also generated wild type Mal and mutant Mal to check whether membrane translocation of Mal is critical for priming of neutrophils.Btk was also involved in regulation of over-production of ROS in eosinophils. We are now working on mast cells derived from Btk deficient patients to examine the role of Btk in production of chymase and tryptase. The role of Itk, Tec family kinase expressed mainly in T cells, in the regulation of ROS production in T cells is currently under investigation.Our data demonstrated the importance of Btk (and Mal) in negative regulation of ROS hyperproduction in granulocytes. Our data so far indicate that PH-domain defective Mal may inhibit priming of neutrophils, and thus the protein may be used for the prevention of hyper-activation of neutrophils in conditions such as sepsis.

Research Products

• [Journal Article] Am80, a retinoic acid receptor agonist, ameliorates murine vasculitis through the suppression of neutrophil migration and activation (2013)
  • Author(s): Miyabe C, Miyabe Y, Miura NN, Takahashi K, Terashima Y, Morio T, Yamagata N, Ohno N, Shudo K, Suzuki J-I, Isobe M, Matsuhima K, Tsuboi R, Miyasaka N, and Nanki T
  • Journal Title: Arthritis Rheumatism Volume: 65 Pages: 503-512
• [Journal Article] Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery ofhumanin (2013)
  • Author(s): Park TY, Kim SH, Shin YC, Lee NH, Lee RK, Shim JH, Glimcher LH, Mook-Jung I, Cheong E, Kim WK, Honda F, Morio T, LimJS, Lee SK
  • Journal Title: J Control Release Volume: 166 Pages: 307-315
• [Journal Article] Am80, a retinoic acid receptor agonist, ameliorates murine vasculitis through the suppression of neutrophil migration and activation (2013)
  • Author(s): Miyabe C, Miyabe Y, Miura NN, Takahashi K, Terashima Y, Toda E, Honda F, Morio T, Yamagata N, Ohno N, Shudo K, Suzuki J, Isobe M, Matsushima K, Tsuboi R, Miyasaka N, Nanki T
  • Journal Title: Arthritis Rheum Volume: 65 Issue: 2 Pages: 503-512
  • DOI: 10.1002/art.37784
  • Peer Reviewed
• [Journal Article] Recurrent mitral valve regurgitation with neutrophil infiltration in a patient with multiple aseptic abscesses (2012)
  • Author(s): Fukuda S, Nanki T, Morio T, Hasegawa H, Koike R, Miyasaka N
  • Journal Title: Mod Rheumatol
• [Journal Article] Btk negatively regulates ROS production and stimulation-induced apoptosis in human neutrophils (2012)
  • Author(s): Honda F, Kano H, Kanegane H, Nonoyama S, Kim E-S, Lee S-K, Takagi M, Mizutani S, Morio T
  • Journal Title: Nature Immunol Volume: 13 Pages: 369-378
• [Journal Article] Impaired cell adhesion, apoptosis, and signaling in WASP-gene disrupted Nalm-6 pre-B cells and recovery of cell adhesion using a transducible form of WASp (2012)
  • Author(s): Sato R, Iiizumi S, Kim E-S, Honda F, Lee S-K, Adachi N, Koyama H, Mizutani S, Morio T
  • Journal Title: Int. J.Hematol Volume: 95 Pages: 299-310
  • NAID: 10030551947
• [Journal Article] The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils (2012)
  • Author(s): Honda F, Kanegane H, et al
  • Journal Title: Nat Immunol Volume: 13 Issue: 4 Pages: 369-378
  • DOI: 10.1038/ni.2234
  • Peer Reviewed
• [Journal Article] Impaired cell adhesion, apoptosis, and signaling in WASP-gene disrupted Nalm-6 pre-B cells and recovery of cell adhesion using a transducible form of WASp. (2012)
  • Author(s): Sato R, Iiizumi S, Kim E-S, Honda F, Lee S-K, Adachi N, Koyama H, Mizutani S, Morio T.
  • Journal Title: Int. J. Hematol. Volume: 95 Issue: 3 Pages: 299-310
  • DOI: 10.1007/s12185-012-1013-1
  • NAID: 10030551947
  • Peer Reviewed
• [Journal Article] Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery. (2012)
  • Author(s): Lee SW, Kim JH, Park MC, Park YB, Chae WJ, Morio T, Lee DH, Yang SH, Lee SK, Lee SK, Lee SK.
  • Journal Title: Biomaterials. Volume: 33 Issue: 5 Pages: 1563-72
  • DOI: 10.1016/j.biomaterials.2011.10.079
  • Peer Reviewed
• [Journal Article] Transducible form of p47phox and p67phox compensate for defective NADPH oxidase activity in neutrophils of patients with chronic granulomatous disease. (2012)
  • Author(s): Honda F, Hane Y, Toma T, Yachie A, Kim E-S, Lee S-K, Takagi M, Mizutani S, Morio T.
  • Journal Title: Biochem. Biophys. Res. Comm. Volume: 417 Issue: 1 Pages: 162-168
  • DOI: 10.1016/j.bbrc.2011.11.077
  • Peer Reviewed
• [Journal Article] Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery. (2012)
  • Author(s): Lee SW, Kim JH, Park MC, Park YB, Chae WJ, Morio T, Lee DH, Yang SH, Lee SK, Lee SK, Lee SK.
  • Journal Title: Biomaterials Volume: 33 Pages: 1563-7
• [Presentation] Btk is a critical gatekeeper of neutrophil responses (2012)
  • Author(s): Morio T
  • Organizer: Medical Immunology World Initiative (MIWI) projects
  • Place of Presentation: 横浜
  • Year and Date: 2012-05-22
• [Presentation] Primary Immunodeficiencies due the Defect in Signaling Molecules (2012)
  • Author(s): Morio T
  • Organizer: 2012 KSMCB Annual Meeting
  • Place of Presentation: Seoul, Korea
• [Presentation] An old and new regulator of ROS production in neutrophils (2012)
  • Author(s): Morio T
  • Organizer: Seminar of Brain Korea 21 Project for Functional Foodsand Nutrigenomics
  • Place of Presentation: Seoul, Korea
• [Presentation] 先天性免疫不全症の病態解析,およびタンパク導入法を用いた治療法の探索 (2012)
  • Author(s): 尾崎富美子、狩野博嗣、金兼弘和、野々山恵章、Sang-Kyou Lee、高木正稔、水谷修紀、森尾友宏
  • Organizer: 第40回日本臨床免疫学会総会
  • Place of Presentation: 東京
• [Presentation] Primary Immunodeficiencies due the Defect in Signaling Molecules. (2012)
  • Author(s): T Morio.
  • Organizer: 2012 KSMCB Annual Meeting.
  • Place of Presentation: Seoul, Korea
• [Presentation] 分類不能型免疫不全症の病態解明へのアプローチ (2011)
  • Author(s): 森尾友宏
  • Organizer: 第39回日本臨床免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-09-17
• [Presentation] 先天性免疫不全症および血液系腫瘍において診断の手がかりとなる皮膚病変と、診断への道筋
  • Author(s): 森尾友宏
  • Organizer: 第36回日本小児皮膚科学会学術大会
  • Place of Presentation: 前橋市