Mechanisms of phenotypic changes in macrophages during tissue injury

• Project/Area Number: 17H04068
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• 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)
• Co-Investigator(Kenkyū-buntansha): 大村谷 昌樹 兵庫医科大学, 医学部, 教授 (60398229)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: マクロファージ / 組織傷害 / 形質転換 / 単球 / 組織修復 / がん / 炎症 / 転写因子

Outline of Final Research Achievements

Macrophages play diverse roles in tissue injury. However, it remains unknown how these macrophages change phenotype according to each phase of tissue injury. This research aimed to reveal mechanisms of phenotypic changes in macrophages during tissue injury. As a result, we demonstrated that two transcriptional factors, c-Maf and Nrf2, determine the phenotype of CD169 macrophages during tissue injury. Furthermore, we identified a novel subpopulation of Ly6C-positive monocytes (Ym1- positive monocytes) in mice. Ym1-positive monocytes are generated in bone marrow during the phase of tissue repair, and contribute to resolution of inflammation and tissue repair in damaged tissues.

Academic Significance and Societal Importance of the Research Achievements

マクロファージは、組織傷害や炎症時に、外界の刺激や環境に素早く対応し、機能的、構造的な変化を起こすことが知られているが、その分子機構は不明な点が多かった。本研究の成果は、特定の転写因子がマクロファージの形質転換に分子スイッチとして働くことを明確に示しており、マクロファージの可塑性および組織傷害の病理を理解する上で有用な知見である。また、得られた知見は将来的に、炎症制御や組織修復促進を目的とした新たな疾患治療法の開発につながる可能性がある。

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] MT1-MMP recruits the ER-Golgi SNARE Bet1 for efficient MT1-MMP transport to the plasma membrane. (2019)
  • Author(s): Miyagawa, T.,* Hasegawa, K.,* Aoki, Y.,* Watanabe, T.,* Otagiri, Y., Arasaki, K., Wakana, Y., Asano, K., Tanaka, M., Yamaguchi, H., Tagaya, M. and Inoue, H. (*, These authors contributed equally to this work.)
  • Journal Title: J. Cell Biol. Volume: 218 Issue: 10 Pages: 3355-3371
  • DOI: 10.1083/jcb.201808149
  • Peer Reviewed / Open Access
• [Journal Article] Lymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage Niche (2019)
  • Author(s): Camara Abdouramane、Cordeiro Olga G.、Alloush Farouk、Sponsel Janina、Chypre M?lanie、Onder Lucas、Asano Kenichi、Tanaka Masato、Yagita Hideo、Ludewig Burkhard、Flacher Vincent、Mueller Christopher G.
  • Journal Title: Immunity Volume: 50 Issue: 6 Pages: 1467-1481.e6
  • DOI: 10.1016/j.immuni.2019.05.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis. (2019)
  • Author(s): K. Dodo, E*. Kuboki*, T Shimizu* (*equally contributed first author), R. Imamura, M. Magarisawa, M. Takahashi, T. Tokuhiro, S. Yasumoto, K. Asano, S. Nakao, N. Terayama, T.Suda, M. Tanaka, M. Sodeoka.
  • Journal Title: ACS Med Chem Lett. Volume: 10 Issue: 9 Pages: 1272-1278
  • DOI: 10.1021/acsmedchemlett.9b00142
  • Peer Reviewed / Open Access
• [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
• [Presentation] 好中球細胞外トラップ形成における脂質酸化の関与 (2019)
  • Author(s): 田中正人
  • Organizer: 第20回Pharmaco-Hemotologyシンポジウム
  • Invited
• [Presentation] ネトーシスにおけるリン脂質酸化の関与 (2019)
  • Author(s): 田中正人
  • Organizer: 第92回日本生化学会大会
• [Presentation] 免疫制御性単球の同定と組織傷害における役割 (2019)
  • Author(s): 田中正人
  • Organizer: 第40回日本炎症再生医学会シンポジウム
  • Invited
• [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
• [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, et al.
  • Total Pages: 183
  • Publisher: SPRINGER-VERLAG
  • ISBN: 9783319239125