Possible roles of eosinophil-sensory nerve communication in itch

• Project/Area Number: 19K17817
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Juntendo University
• Principal Investigator: Toyama Sumika 順天堂大学, 医学(系)研究科(研究院), 博士研究員 (50805893)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 好酸球 / 感覚神経 / アトピー性皮膚炎 / 痒み / 難治性痒み / 神経線維 / 免疫細胞

Outline of Research at the Start

アトピー性皮膚炎(AD)は強い痒みのある湿疹を主病変とする慢性炎症性皮膚疾患である。その痒みは難治性痒みと言われ、患者のQOLを著しく低下させる。AD炎症局所において、感覚神経線維が増生していることが難治性痒みの一因と言われている。一方、AD炎症局所には免疫細胞が浸潤していることから、神経線維と接触することで相互に作用し、痒み過敏を増強することが考えられるが、その詳細は不明瞭である。本研究では、免疫細胞、特に好酸球及びその分化・活性化を制御するILC2に着眼し、免疫細胞と感覚神経線維の接触による相互作用の観点から、ADにおける痒み発現発症メカニズムの解明と、新規治療法及び予防法の開発を目指す。

Outline of Final Research Achievements

We set up a co-culture system of sensory neurons and eosinophils in this study. As a result of co-culture sensory nerve cells and eosinophils using this system, the sensory nerves regressed. In addition, then eosinophils promoted cell death. Moreover, activated eosinophils increased expression of chemokine and cell adhesion factors. In migration assay, sensory nerves attenuated the migration of eosinophils.
From the above results, eosinophils migrate to lesion, but their motility is attenuated by the sensory nerve-derived components, and after adhering to the sensory nerves, cell death occurs and nerve fibers are damaged.

Academic Significance and Societal Importance of the Research Achievements

これまで感覚神経と好酸球がAD炎症局所にそれぞれ存在していることは報告されていた。しかしながらこれらが近接している報告はなく、本研究結果により、両者が近接していることを確認した点で新規性及び独自性が高い。また共培養系の結果から、感覚神経線維に接着した好酸球は、その場で細胞死を起こし、神経線維を傷害することで感覚神経線維を退縮させると示唆された。
本研究成果は、好酸球と感覚神経線維の相互作用を標的としたADの新規治療法に向け、将来的に本研究成果は社会貢献に繋がる発展性の高い研究といえる。

Research Products

• [Journal Article] Calcium-inducible MAPK/AP-1 signaling drives semaphorin 3A expression in normal human epidermal keratinocytes. (2020)
  • Author(s): Kamata Y, Tominaga M, Umehara Y, Honda K, Kamo A, Moniaga CS, Komiya E, Toyama S, Suga Y, Ogawa H, Takamori K
  • Journal Title: J Invest Dermatol. Volume: ー Issue: 7 Pages: 1346-1354
  • DOI: 10.1016/j.jid.2020.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia (2020)
  • Author(s): Unno Hirotoshi、Arae Ken、Matsuda Akira、Ikutani Masashi、Tamari Masato、Motomura Kenichiro、Toyama Sumika、Suto Hajime、Okumura Ko、Matsuda Akio、Morita Hideaki、Sudo Katsuko、Saito Hirohisa、Matsumoto Kenji、Nakae Susumu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 533 Issue: 3 Pages: 493-500
  • DOI: 10.1016/j.bbrc.2020.09.046
  • Peer Reviewed / Open Access
• [Journal Article] Robust induction of neural crest cells to derive peripheral sensory neurons from human induced pluripotent stem cells (2020)
  • Author(s): Umehara Yoshie、Toyama Sumika、Tominaga Mitsutoshi、Matsuda Hironori、Takahashi Nobuaki、Kamata Yayoi、Niyonsaba Francois、Ogawa Hideoki、Takamori Kenji
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4360-4360
  • DOI: 10.1038/s41598-020-60036-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A method for induction of peripheral sensory neurons from human induced pluripotent stem cells. (2021)
  • Author(s): Sumika Toyama, Yoshie Umehara, Mitsutoshi Tominaga, Kenji Takamori.
  • Organizer: 第29回国際痒みシンポジウム
  • Int'l Joint Research
• [Presentation] Kinetic analysis of regulatory T cells in skin barrier disruption. (2020)
  • Author(s): Sumika Toyama, Catharina Sagita Moniaga, Mitsutoshi Tominaga, Hideoki Ogawa, Kenji Takamori.
  • Organizer: 第45回 日本研究皮膚科学会
• [Presentation] Endomorphin preferentially induces mechanical alloknesis under the enzymatic control of DPPIV. (2020)
  • Author(s): Eriko Komiya, Ryo Hatano, Takumi Itoh, Kotaro Honda, Yayoi Kamata, Sumika Toyama, Catharina Sagita Moniaga,Haruna Otsuka, Kei Ohnuma, Mitsutoshi Tominaga, Chikao Morimoto, Kenji Takamori.
  • Organizer: 第45回 日本研究皮膚科学会
• [Presentation] カルシウムイオン濃度は正常ヒト表皮におけるセマフォリン3A遺伝子の発現制御に関与する (2020)
  • Author(s): 鎌田弥生、冨永光俊、本田耕太郎、Catharina Sagita Moniaga、古宮栄利子、外山扇雅、髙森建二
  • Organizer: 第38回サイトプロテクション研究会
• [Presentation] Regulatory T cells (Tregs) modulate skin homeostasis to release inhibitory cytokines. (2020)
  • Author(s): RegulSumika Toyama, Catharina Sagita Moniaga, Mitsutoshi Tominaga, Kenji Takamori.
  • Organizer: JSA/WAO Joint Congress 2020.
  • Int'l Joint Research
• [Presentation] ossible roles of eosinophil-sensory nerve communication in atopic dermatitis. (2019)
  • Author(s): Toyama S, Ogawa H, Suga Y, Tominaga M, Takamori K.
  • Organizer: 第15回 Tokyo Scientific Forum for Atopic Dermatitis and Psoriasis (TAP)
  • Invited
• [Presentation] Possible regulation of mechanical itch by CD26/DPPIV. (2019)
  • Author(s): Komiya E, Hatano R, Itoh T, Otsuka H, Kamata Y, Honda K, Toyama S, C, Ohnuma K, Tominaga M, Morimoto C, Takamori K.
  • Organizer: The 10th World Congress on Itch, Sydney
  • Int'l Joint Research
• [Presentation] Calcium/MEK1/2/AP-1 signaling axis induces semaphorin 3A expression in normal human epidermal keratinocytes. (2019)
  • Author(s): Kamata Y, Tominaga M, Umehara Y, Honda K, Kamo A, Moniaga C, Komiya E, Toyama S, Suga Y, Takamori K.
  • Organizer: The 10th World Congress on Itch, Sydney
  • Int'l Joint Research
• [Presentation] Possible role for CD26/DPPIV in regulating mechanical itch (Alloknesis) (2019)
  • Author(s): Komiya-Suyama E, Hatano R, Itoh T, Otsuka H, Kamata Y, Honda K, Toyama S, Moniaga C, Ohnuma K, Tominaga M, Morimoto C, Takamori K.
  • Organizer: 28th European Academy of Dermatology and Venereology
  • Int'l Joint Research
• [Presentation] Elucidation of the signaling pathway involved in Sema3A gene expression in normal human epidermal keratinocytes. (2019)
  • Author(s): Kamata Y, Tominaga M, Umehara Y, Honda K, Kamo A, Toyama S, Suga Y, Takamori K.
  • Organizer: 28th European Academy of Dermatology and Venereology
  • Int'l Joint Research
• [Presentation] CD26/ dipeptidyl-peptidase IVは機械的かゆみの抑制因子である (2019)
  • Author(s): 古宮栄利子、波多野良、冨永光俊、伊藤匠、鎌田弥生、本田耕太郎、外山扇雅、カタリナ サギタ モニアガ、大沼圭、森本幾夫、高森建二
  • Organizer: 日本病態プロテアーゼ学会
• [Presentation] Possible roles of eosinophil-sensory nerve communication in atopic dermatitis. (2019)
  • Author(s): Toyama S, Sato-Fukami R, Ogawa H, Suga Y, Tominaga M, Takamori M.
  • Organizer: 第118回 日本皮膚科学会総会
• [Book] 痒みのメカニズム～皮膚から脊髄まで～ (2019)
  • Author(s): 冨永光俊、外山扇雅、古宮栄利子、鎌田弥生、髙森建二
  • Total Pages: 7
  • Publisher: 日本臨床皮膚科医会雑誌