Research

1. Roles of TLRs in the recognition of microbial products and the regulation of innate immune responses

①LPS recognition and responses by TLR4/MD-2 complex and RP105/MD-1 complex

  • Requirement of MD-1 in cell surface expression of RP105/CD180 and B cell responsiveness to lipopolysaccahride.
    Nagai Y, Shimazu R, Ogata H, Akshi S, Sudo K, Yamasaki H, Hayashi S-I, Iwakura Y, Kimoto M, Miyake K.
    Blood. 99(5):1699-1705,2002.
    https://www.ncbi.nlm.nih.gov/pubmed/11861286
  • Essential role of MD-2 in LPS responsiveness and TLR4 distribution.
    Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, Kitamura T, Kosugi A, Kimoto M, Miyake K.
    Nat. Immunol. 3(7):667-672,2002.
    https://www.ncbi.nlm.nih.gov/pubmed/12055629
  • The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD2 in antibody response to microbial membranes.
    Nagai Y, Kobayashi T, Motoi Y, Ishiguro K, Akashi S, Saitoh S, Kusumoto Y, Kaisho T, Akira S, Matsumoto M, Takatsu K, Miyake K.
    J. Immunol. 174(11):7043-7049,2005.
    https://www.ncbi.nlm.nih.gov/pubmed/15905547
  • The RP105/MD-1 complex is indispensable for TLR4/MD-2-dependent proliferation and IgM-secreting plasma cell differentiation of marginal zone B cells.
    Nagai Y, Yanagibashi T, Watanabe Y, Ikutani M, Kariyone A, Ohta S, Hirai Y, Kimoto M, Miyake K, Takatsu K.
    Int. Immunol. 24(6):389-400,2012.
    https://www.ncbi.nlm.nih.gov/pubmed/22354914

②Roles of TLR signaling in class switch recombination and antibody production in B cells.

  • Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production.
    Tsukamoto Y, Nagai Y, Kariyone A, Shibata T, Kaisho T, Akira S, Miyake K, Takatsu K.
    Mol. Immunol. 46(7):1278-1288,2009.
    https://www.ncbi.nlm.nih.gov/pubmed/19157556
  • Differential requirements of MyD88 and TRIF pathways in TLR4-mediated immune responses in murine B cells.
    Yanagibashi T, Nagai Y, Watanabe Y, Ikutani M, Hirai Y, Takatsu K.
    Immunol. Lett. 163(1):22-31,2015.
    https://www.ncbi.nlm.nih.gov/pubmed/25448706

2. Analysis of TLR signaling in the development of chronic inflammatory diseases

  • Serum soluble MD-1 levels increase with disease progression in autoimmune prone MRL(lpr/lpr) mice.
    Sasaki S, Nagai Y, Yanagibashi T, Watanabe Y, Ikutani M, Kariyone A, Tsuneyama K, Hirai Y, Takatsu K.
    Mol. Immunol. 49(4):611-620,2012.
    https://www.ncbi.nlm.nih.gov/pubmed/22118968
  • The Radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation.
    Watanabe Y, Nakamura T, Ishikawa S, Fujisaka S, Usui I, Tsuneyama K, Ichihara Y, Wada T, Hirata Y, Suganami T, Izaki H, Akira S, Miyake K, Kanayama H, Shimabukuro M, Sata M, Sasaoka T, Ogawa Y, Tobe K, Takatsu K, Nagai Y.
    Diabetes. 61(5):1199-1209,2012.
    https://www.ncbi.nlm.nih.gov/pubmed/22396206
  • The TLR family protein RP105/MD-1 complex: A new player in obesity and adipose tissue inflammation.
    Nagai Y, Watanabe Y, Takatsu K.
    Adipocyte. 2(2) :61-66, 2013.

    http://www.ncbi.nlm.nih.gov/pubmed/23805400
  • Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance.
    Watanabe Y, Nagai Y, Takatsu K.
    Nutrients. 5(9): 3757-3778, 2013.
    http://www.ncbi.nlm.nih.gov/pubmed/24064574

3. Development of new drugs by utilizing natural products and compounds that regulate innate immune system

  • Glycyrrhizin and isoliquiritigenin suppress the LPS sensor toll-like receptor 4/MD-2 complex signaling in a different manner.
    Honda H, Nagai Y, Matsunaga T, Saitoh S, Akashi-Takamura S, Hayashi H, Fujii I, Miyake K, Muraguchi A, Takatsu K.
    J. Leukoc. Biol. 91(6):967-976,2012.
    https://www.ncbi.nlm.nih.gov/pubmed/22422925
  • Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation.
    Honda H, Nagai Y, Matsunaga T, Okamoto N, Watanabe Y, Tsuneyama K, Hayashi H, Fujii I, Ikutani M, Hirai Y, Muraguchi A, Takatsu K.
    J. Leukoc. Biol. 96(6):1087-1100,2014.
    https://www.ncbi.nlm.nih.gov/pubmed/25210146
  • Isoliquiritigenin attenuates an inflammatory paracrine loop between adipocytes and macrophages and adipose tissue fibrosis through inhibition of innate immune responses.
    Watanabe Y, Nagai Y, Honda H, Okamoto N, Yamamoto S, Hamashima T, Ishii Y, Tanaka M, Suganami T, Sasahara M, Miyake K, Takatsu K.
    Sci. Rep. 6:Article number: 23097 (2016) doi: 10.1038/srep23097
    https://www.ncbi.nlm.nih.gov/pubmed/26975571
  • Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex.
    Okamoto N, Mizote K, Honda H, Saeki A, Watanabe Y, Yamaguchi-Miyamoto T, Fukui R, Tanimura N, Motoi Y, Akashi-Takamura S, Kato T, Fujishita S, Kimura T, Ohto U, Shimizu T, Hirokawa T, Miyake K, Fukase K, Fujimoto Y, Nagai Y, Takatsu K.
    J. Biol. Chem, 2017 Sep 15;292(37):15378-15394.
    https://www.ncbi.nlm.nih.gov/pubmed/28754693

4. Roles of TLR signaling in hematopoietic development

  • oll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment.
    Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, Takatsu K,  Kincade PW.
    Immunity. 24(6):801-812,2006.
    https://www.ncbi.nlm.nih.gov/pubmed/16782035
  • Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection.
    Welner RS, Pelayo R, Nagai Y, Garrett KP, Wuest TR, Carr DJ, Borqhesi LA, Farrar MA, Kincade PW.
    Blood. 112(9):3753-3761,2008.
    https://www.ncbi.nlm.nih.gov/pubmed/18552210
  • Life before the pre-B cell receptor checkpoint: specification and commitment of primitive lymphoid progenitors in adult bone marrow.
    Pelayo R, Welner RS, Nagai Y, Kincade PW.
    Semin. Immunol. 18(1), 2-11, 2006.
    https://www.ncbi.nlm.nih.gov/pubmed/16310376
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