Mechanisms of immunoregulation by dead cell clearance

• Project Area: Homeostatic Regulation by Various Types of Cell Death
• Project/Area Number: 26110006
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Tanaka Masato 東京薬科大学, 生命科学部, 教授 (00294059)
• Research Collaborator: ASANO Kenichi 東京薬科大学, 生命科学部, 准教授 (10513400) ; OIKAWA Akira 国立研究開発法人理化学研究所, 環境資源科学研究センター, 客員研究員 (50442934)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥128,050,000 (Direct Cost: ¥98,500,000、Indirect Cost: ¥29,550,000); Fiscal Year 2018: ¥24,310,000 (Direct Cost: ¥18,700,000、Indirect Cost: ¥5,610,000); Fiscal Year 2017: ¥25,610,000 (Direct Cost: ¥19,700,000、Indirect Cost: ¥5,910,000); Fiscal Year 2016: ¥25,610,000 (Direct Cost: ¥19,700,000、Indirect Cost: ¥5,910,000); Fiscal Year 2015: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000); Fiscal Year 2014: ¥27,820,000 (Direct Cost: ¥21,400,000、Indirect Cost: ¥6,420,000)
• Keywords: 細胞死 / マクロファージ / 貪食

Outline of Final Research Achievements

This project aimed to reveal the molecular mechanisms of immunoregulation by dead cell clearance played by macrophages, and obtained following findings; 1. We revealed roles of intestinal CD169-positive macrophages in colitis, and identified the transcriptional factor regulating the function of these macrophages. 2. We revealed the regulatory mechanisms of neutrophil function by macrophages, and the molecular mechanisms of netosis. 3. We identified novel monocyte subset that contributes to repair of injured tissues.

Academic Significance and Societal Importance of the Research Achievements

死細胞処理と炎症制御を担う腸管マクロファージの機能分子の同定とその発現制御機構が解明されたこと、および、組織修復に寄与する新規単球サブセットの同定に成功したことから、生体内の細胞死に対する自然免疫応答の一端が明らかとなった。また、好中球から放出されるダイイングコードの同定と機能の解明にも成功し、将来の組織傷害に対する治療法開発に道をつけることができた。

Research Products

• [Journal Article] Maea expressed by macrophages, but not erythroblasts, maintains postnatal murine bone marrow erythroblastic islands (2019)
  • Author(s): Wei Q, Boulais PE, Zhang D, Pinho S, Tanaka M, Frenette PS.
  • Journal Title: Blood Volume: 133 Issue: 11 Pages: 1222-1232
  • DOI: 10.1182/blood-2018-11-888180
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation (2018)
  • Author(s): Kikuchi Kenta、Iida Mayumi、Ikeda Naoki、Moriyama Shigetaka、Hamada Michito、Takahashi Satoru、Kitamura Hiroshi、Watanabe Takashi、Hasegawa Yoshinori、Hase Koji、Fukuhara Takeshi、Sato Hideyo、Kobayashi Eri H.、Suzuki Takafumi、Yamamoto Masayuki、Tanaka Masato、Asano Kenichi
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 2 Pages: 635-651
  • DOI: 10.4049/jimmunol.1800040
  • Peer Reviewed / Open Access
• [Journal Article] Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury (2018)
  • Author(s): Ikeda Naoki、Asano Kenichi、Kikuchi Kenta、Uchida Yoshimi、Ikegami Hiroki、Takagi Ryo、Yotsumoto Satoshi、Shibuya Takumi、Makino-Okamura Chieko、Fukuyama Hidehiro、Watanabe Takashi、Ohmuraya Masaki、Araki Kimi、Nishitai Gen、Tanaka Masato
  • Journal Title: Science Immunology Volume: 3 Issue: 28
  • DOI: 10.1126/sciimmunol.aat0207
  • Peer Reviewed
• [Journal Article] Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice. (2018)
  • Author(s): Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H.
  • Journal Title: Biochemical Biophysical Research Communications Volume: 505 Issue: 2 Pages: 453-459
  • DOI: 10.1016/j.bbrc.2018.09.128
  • Peer Reviewed / Open Access
• [Journal Article] CD169 macrophages regulate immune responses toward particulate materials in the circulating fluid. (2018)
  • Author(s): Asano K, Kikuchi K, Tanaka M.
  • Journal Title: J Biochem Volume: 164 Issue: 2 Pages: 77-85
  • DOI: 10.1093/jb/mvy050
  • Peer Reviewed / Open Access
• [Journal Article] Tumor Necrosis Factor-Mediated Survival of CD169(+) Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection. (2017)
  • Author(s): Shinde PV, Xu HC, Maney SK, Kloetgen A, Namineni S, Zhuang Y, Honke N, Shaabani N, Bellora N, Doerrenberg M, Trilling M, Pozdeev VI, van Rooijen N, Scheu S, Pfeffer K, Crocker PR, Tanaka M, Duggimpudi S, Knolle P, Heikenwalder M, Ruland J, Mak TW, Brenner D, Pandyra AA, Hoell JI, Borkhardt A, Haussinger D, Lang KS
  • Journal Title: J Virol Volume: 92 Issue: 3 Pages: 01637-01637
  • DOI: 10.1128/jvi.01637-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation (2017)
  • Author(s): Yotsumoto Satoshi、Muroi Yuito、Chiba Tatsuya、Ohmura Rio、Yoneyama Maki、Magarisawa Megumi、Dodo Kosuke、Terayama Naoki、Sodeoka Mikiko、Aoyagi Ryohei、Arita Makoto、Arakawa Satoko、Shimizu Shigeomi、Tanaka Masato
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 16026-16026
  • DOI: 10.1038/s41598-017-15668-z
  • Peer Reviewed / Open Access
• [Journal Article] Macrophage Subset Expressing CD169 in Peritoneal Cavity-Regulated Mucosal Inflammation Together with Lower Levels of CCL22. (2017)
  • Author(s): Wang D, Li Q, Yang Y, Hao S, Han X, Song J, Yin Y, Li X, Tanaka M, Qiu CH.
  • Journal Title: Inflammation Volume: 40 Issue: 4 Pages: 1191-203
  • DOI: 10.1007/s10753-017-0562-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum (2017)
  • Author(s): Piao, X. Yamazaki, S. Komazawa-Sakon, S. Miyake, S. Nakabayashi, O. Kurosawa, T. Mikami, T. Tanaka, M. Van Rooijen, N. Ohmuraya, M. Oikawa, A. Kojima, Y. Kakuta, S. Uchiyama, Y. Tanaka, M. Nakano, H.
  • Journal Title: Hepatology Volume: 65 Issue: 1 Pages: 237-252
  • DOI: 10.1002/hep.28878
  • NAID: 120006528815
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CD169+ macrophages orchestrate innate immune responses by regulating bacterial localization in the spleen. (2017)
  • Author(s): Perez OA, Yeung ST, Vera-Licona P, Romagnoli PA, Samji T, Ural BB, Maher L, Tanaka M, Khanna KM.
  • Journal Title: Sci Immunol Volume: 2 Issue: 16 Pages: 1-12
  • DOI: 10.1126/sciimmunol.aah5520
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD169 Expressing Macrophage, a Key Subset in Mesenteric Lymph Nodes Promotes Mucosal Inflammation in Dextran Sulfate Sodium-Induced Colitis (2017)
  • Author(s): Li Q, Wang D, Hao S, Han X, Xia Y, Li X, Chen Y, Tanaka M, Qiu CH.
  • Journal Title: Front Immunol Volume: 8 Pages: 669-669
  • DOI: 10.3389/fimmu.2017.00669
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis (2017)
  • Author(s): Itoh Michiko、Suganami Takayoshi、Kato Hideaki、Kanai Sayaka、Shirakawa Ibuki、Sakai Takeru、Goto Toshihiro、Asakawa Masahiro、Hidaka Isao、Sakugawa Hiroshi、Ohnishi Koji、Komohara Yoshihiro、Asano Kenichi、Sakaida Isao、Tanaka Masato、Ogawa Yoshihiro
  • Journal Title: JCI Insight Volume: 2 Issue: 22 Pages: 1-16
  • DOI: 10.1172/jci.insight.92902
  • Peer Reviewed / Open Access
• [Journal Article] Salt suppresses IFNγ inducible chemokines through the IFNγ-JAK1-STAT1 signaling pathway in proximal tubular cells. (2017)
  • Author(s): Arai Y, Takahashi D, Asano K, Tanaka M, Oda M, Ko SBH, Ko MSH, Mandai S, Nomura N, Rai T, Uchida S, Sohara E.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 46580-46580
  • DOI: 10.1038/srep46580
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Programmed cell death and the immune system. (2017)
  • Author(s): Nagata S, Tanaka M.
  • Journal Title: Nat Rev Immunol. Volume: 17 Issue: 5 Pages: 333-340
  • DOI: 10.1038/nri.2016.153
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF (2016)
  • Author(s): T. Yoshida, M. Tsujioka, S. Honda, S. Shimizu
  • Journal Title: Oncotarget Volume: 7 Issue: 23 Pages: 34420-9
  • DOI: 10.18632/oncotarget.8883
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of B cell differentiation by the ubiquitin-binding protein TAX1BP1. (2016)
  • Author(s): Matsushita, N., Suzuki, M., Ikebe, E., Nagashima, S., Inatome, R., Asano, K., Tanaka, M., Matsushita, M., Kondo, E., Iha, H., and Yanagi, S.
  • Journal Title: Sci. Rep Volume: 6 Issue: 1 Pages: 31266-31266
  • DOI: 10.1038/srep31266
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Immune Regulation by Dead Cell Clearance. (2015)
  • Author(s): Tanaka M, Nishitai G.
  • Journal Title: Current Topics in Microbiology and Immunology Volume: ※ Pages: 1-13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of Pathogenic Cardiac CD11c+ Macrophages in Nod1-Mediated Acute Coronary Arteritis. (2015)
  • Author(s): Motomura Y, et al.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 35 Issue: 6 Pages: 1423-33
  • DOI: 10.1161/atvbaha.114.304846
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vascular‐resident CD169‐positive Monocytes and Macrophages Control Neutrophil Accumulation in the Kidney with Ischemia‐reperfusion Injury. (2015)
  • Author(s): Karasawa K, Asano K, Moriyama S, Ushiki M, Monya M, Iida M, Kuboki E, Yagita H, Uchida K, Nitta K, Tanaka M.
  • Journal Title: J. Am. Soc. Nephrol. Volume: ２６（４） Issue: 4 Pages: 896-906
  • DOI: 10.1681/asn.2014020195
  • Peer Reviewed / Open Access
• [Journal Article] γ-SNAP stimulates disassembly of endosomal SNARE complexes and regulates endocytic trafficking pathways. (2015)
  • Author(s): Inoue, H., Matsuzaki, Y., Tanaka, A., Hosoi, K., Ichimura, K., Arasaki, K., Wakana, Y., Asano, K., Tanaka, M., Okuzaki, D., Yamamoto, A., Tani, K. and Tagaya, M.
  • Journal Title: J. Cell Sci. Volume: 128 Pages: 2781-2794
  • DOI: 10.1242/jcs.158634
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intestinal CD169+macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes (2015)
  • Author(s): Kenichi Asano, Naomichi Takahashi, Mikiko Ushiki, Misa Monya, Fumiaki Aihara, Erika Kuboki,Shigetaka Moriyama,Mayumi Iida,Hiroshi Kitamura, Chun-Hong Qiu,Takashi Watanabe, Masato Tanaka
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 7802-7802
  • DOI: 10.1038/ncomms8802
  • NAID: 120006311913
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Colony-StimulatingFactor-1 Signaling Suppresses Renal Crystal Formation. (2015)
  • Author(s): Taguchi Kazumi, Okada Atsushi, Kitamura Hiroshi, Yasui Takahiro, Naiki Taku, Hamamoto Shuzo, Ando Ryosuke, Mizuno Kentaro, Kawai Noriyasu, Tozawa Keiichi, Asano Kenichi, Tanaka Masato, Miyoshi Ichiro, Kohri Kenjiro
  • Journal Title: Journal of the American Society of Nephrology Volume: 25 Issue: 8 Pages: 1680-1697
  • DOI: 10.1681/asn.2013060675
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria. (2014)
  • Author(s): Yonekawa A, Saijo S, Hoshino Y, Miyake Y, Ishikawa E, Suzukawa M, Inoue H, Tanaka M, Yoneyama M, Oh-Hora M, Akashi K, Yamasaki S.
  • Journal Title: Immunity Volume: 41 Issue: 3 Pages: 402-13
  • DOI: 10.1016/j.immuni.2014.08.005
  • Peer Reviewed / Open Access
• [Journal Article] Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance (2014)
  • Author(s): Ravishankar, B., Tanaka, M. (他9名)
  • Journal Title: Proc Natl Acad Sci USA Volume: 111(11) Issue: 11 Pages: 4215-20
  • DOI: 10.1073/pnas.1320924111
  • Peer Reviewed / Open Access
• [Presentation] The role of immunoregulatory monocytes in the recovery phase of tissue injury (2018)
  • Author(s): 田中正人
  • Organizer: Australia-Japan Meeting on Cell Death
  • Int'l Joint Research
• [Presentation] Resolution of inflammation and tissue repair by immunoregulatory monocytes. (2018)
  • Author(s): 田中正人
  • Organizer: Cytokines2018
  • Int'l Joint Research / Invited
• [Presentation] ネトーシスと脂質酸化 (2017)
  • Author(s): 田中正人
  • Organizer: 第26回 日本Cell Death学会
• [Presentation] 酸化脂質によるneutrophil extracellular trap の形成 (2017)
  • Author(s): 田中正人
  • Organizer: 生命科学系学会合同年次大会
• [Presentation] Immuneregulation by CD169 Macrophages (2016)
  • Author(s): 田中正人
  • Organizer: MMCB2016
  • Place of Presentation: ソラシティ カンファレンスセンター
  • Int'l Joint Research / Invited
• [Presentation] The role of CD169 macrophages in the regulation of inflammation (2016)
  • Author(s): 田中正人
  • Organizer: IMS-JSI国際シンポジウム2016
  • Place of Presentation: パシフィコ横浜
  • Int'l Joint Research / Invited
• [Presentation] 組織傷害におけるCD169マクロファージの役割 (2016)
  • Author(s): 田中正人
  • Organizer: Ｃｅｌｌ Ｄｅａｔｈ 学会
  • Place of Presentation: きゅりあん品川
• [Presentation] CD169陽性マクロファージによる死細胞貪食と炎症制御 (2016)
  • Author(s): 田中正人
  • Organizer: 第89回 生化学会大会
  • Place of Presentation: 仙台国際センター
• [Presentation] 組織マクロファージによる炎症制御機構 (2016)
  • Author(s): 田中正人
  • Organizer: 第31回日本Shock学会総会
  • Place of Presentation: 東京ドームホテル
• [Presentation] CD170陽性マクロファージによる死細胞貪食と免疫制御 (2016)
  • Author(s): 田中正人
  • Organizer: 千里ライフサイエンスセミナーK4
  • Place of Presentation: 千里ライフサイエンスセンタービル
  • Invited
• [Presentation] 細胞死を起点とする生体応答 (2015)
  • Author(s): 田中正人
  • Organizer: 第44回 日本免疫学会
  • Place of Presentation: SORA札幌コンベンションセンター
  • Year and Date: 2015-11-20
• [Presentation] The Role of CD169 Macrophages in immune Regulation (2015)
  • Author(s): 田中正人
  • Organizer: KAI 2015 Fall Conference
  • Place of Presentation: Sejong University Convention Center
  • Year and Date: 2015-11-12
  • Int'l Joint Research / Invited
• [Presentation] 死細胞貪食による免疫制御 (2015)
  • Author(s): 田中正人
  • Organizer: 第31回Wakoワークショップ
  • Place of Presentation: 東京カンファレンスｾﾝﾀｰ・品川
  • Year and Date: 2015-11-04
  • Invited
• [Presentation] The role of CD169 macrophages in dead cell clearance and inflammatory regulation (2015)
  • Author(s): 田中正人
  • Organizer: Japan Australia Meeting on Cell Death
  • Place of Presentation: Walter Eliza Hall
  • Year and Date: 2015-10-21
  • Int'l Joint Research
• [Presentation] CD169マクロファージによる死細胞貪食と炎症制御 (2014)
  • Author(s): 田中正人
  • Organizer: 第23回Cell Death学会
  • Place of Presentation: 東京医科歯科大学
  • Year and Date: 2014-07-18 – 2014-07-19
• [Book] Current Topics in Microbiology & Immunology, Vol.403 p.171-183 Immune Regulation by Dead Cell Clearance. (2017)
  • Author(s): S.Nagata & H.Nakano (eds.) Tanaka M, Nishitai G,
  • Total Pages: 183
  • Publisher: SPRINGER-VERLAG
  • ISBN: 9783319239125