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Bone marrow-derived myeloid cells entering the brain via the choroid plexus are involved in neuroinflammatory and neurodegenerative conditions

Research Project

Project/Area Number 18K07072
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionKyorin University

Principal Investigator

Shimada Atsuyoshi  杏林大学, 保健学部, 教授 (50311444)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords脈絡叢 / 神経炎症 / 敗血症関連脳症 / 全身性炎症 / 脳内炎症 / 敗血症 / ミエロイド系譜 / ミクログリア / ミエロイド系譜細胞 / 頭部間葉 / 脳 / 免疫系 / 骨髄 / 神経変性
Outline of Final Research Achievements

Systemic inflammation such as sepsis is a risk factor for encephalopathy. However, it remains to be revealed how systemic inflammation induces changes in brain microenvironment. In the present study, we aimed to investigate the mechanism underlying systemic inflammation-induced pro-inflammatory changes in the brain microenvironment and to compare the mechanisms between adult and immature brains. Our experimental studies using adult mice indicated that the choroid plexus, a organ to produce cerebrospinal fluid play a key role to transmit systemic inflammation to brain parenchyma by cytokine-mediated intercellular stimulation between stromal and epithelial cells. On the other hand, elevation in the brain tissue cytokine concentration lasted longer in the immature brains when newborn mice were challenged with systemic inflammation. It should be noted that the main cell population involved in the cytokine production were vascular endothelial cells in immature brains.

Academic Significance and Societal Importance of the Research Achievements

敗血症は全世界で年間5000万人もの人々が罹患し、1000万人が死亡する重大な疾患である。ICUで治療を受ける敗血症患者の約50%で脳症状が発生し、重症化の初期徴候であるが、画像上で脳に病変が確認できるのは約50%と謎の多い病態である。とりわけ早産児は免疫力がまだ弱く、敗血症をはじめとする全身性炎症を発症すると、発達途上の脳に何らかの病変が誘発され、脳性麻痺や神経発達症などの後遺障害をのこす。この際に全身性炎症の影響を脳に伝達する機序は不明である。我々は、ヒトでは早産児に相当する新生仔マウスを用いて新生児敗血症モデルを作製し、全身性炎症を脳に伝達する未熟脳に特有な機序の一端を明らかにした。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (30 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (5 results) Journal Article (15 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 14 results,  Open Access: 10 results) Presentation (9 results) (of which Int'l Joint Research: 8 results,  Invited: 3 results) Remarks (1 results)

  • [Int'l Joint Research] University of Illinois(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] RMIT University(オーストラリア)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] China Medical University(中国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Pennsylvania State University/University of Texas(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Pennsylvania State University(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Impaired phosphorylation of c-Ret causes cerebellar hypoplasia in mice with Hirschsprung disease.2021

    • Author(s)
      Ohgami N, Iizuka A, Hirai H, Yajima I, Iida M, Shimada A, Tsuzuki T, Jijiwa M, Asai N, Takahashi M, Kato M
    • Journal Title

      J Biol Chem

      Volume: - Pages: 100389-100389

    • DOI

      10.1016/j.jbc.2021.100389

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sex-dependent differences in the gut microbiota following chronic nasal inflammation in adult mice2021

    • Author(s)
      Mishima Yuko、Osaki Takako、Shimada Atsuyoshi、Kamiya Shigeru、Hasegawa-Ishii Sanae
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 4640-4640

    • DOI

      10.1038/s41598-021-83896-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human papillomavirus infection status of single cells isolated from cervical cytology specimens by simple manual microdissection2021

    • Author(s)
      Noji Natsumi、Okayama Kaori、Oda Mizue、Shimada Atsuyoshi、Okodo Mitsuaki
    • Journal Title

      Journal of Medical Virology

      Volume: 2021 Issue: 8 Pages: 1-11

    • DOI

      10.1002/jmv.26888

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Increased cytokine expression in the choroid plexus stroma and epithelium in response to endotoxin-induced systemic inflammation in mice2021

    • Author(s)
      Shimada Atsuyoshi、Hasegawa-Ishii Sanae
    • Journal Title

      Toxicology Reports

      Volume: 8 Pages: 520-528

    • DOI

      10.1016/j.toxrep.2021.03.002

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutation in Sodium-Glucose Cotransporter 2 Results in Down-Regulation of Amyloid Beta (A4) Precursor-Like Protein 1 in Young Age, Which May Lead to Poor Memory Retention in Old Age2020

    • Author(s)
      Unno Keiko、Takagi Yoshiichi、Konishi Tomokazu、Suzuki Mitsuhiro、Miyake Akiyuki、Kurotaki Takumi、Hase Tadashi、Meguro Shinichi、Shimada Atsuyoshi、Hasegawa-Ishii Sanae、Pervin Monira、Taguchi Kyoko、Nakamura Yoriyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 15 Pages: 5579-5579

    • DOI

      10.3390/ijms21155579

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis2020

    • Author(s)
      Furukawa Ayako、Kakita Akiyoshi、Chiba Yoichi、Kitaura Hiroki、Fujii Yukihiko、Fukuda Masafumi、Kameyama Shigeki、Shimada Atsuyoshi
    • Journal Title

      Epilepsy Research

      Volume: 168 Pages: 106502-106502

    • DOI

      10.1016/j.eplepsyres.2020.106502

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Psychoneuroimmunology goes East: Development of the PNIRS affiliate and its expansion into PNIRS2020

    • Author(s)
      Kelley Keith W.、Peng Yu-Ping、Liu Quentin、Chang Hui-Chih、Spencer Sarah J.、Hutchinson Mark R.、Shimada Atsuyoshi
    • Journal Title

      Brain, Behavior, and Immunity

      Volume: 88 Pages: 75-87

    • DOI

      10.1016/j.bbi.2020.04.026

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 脳と免疫系の細胞間相互作用を可能にする脳の組織学的構築原理2020

    • Author(s)
      島田厚良
    • Journal Title

      杏林医学会雑誌

      Volume: 51巻 Pages: 169-177

    • NAID

      130007922724

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Widespread time-dependent changes in tissue cytokine concentrations in brain regions during the acute phase of endotoxemia in mice2020

    • Author(s)
      Hasegawa-Ishii Sanae、Inaba Muneo、Shimada Atsuyoshi
    • Journal Title

      NeuroToxicology

      Volume: 76 Pages: 67-74

    • DOI

      10.1016/j.neuro.2019.10.006

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Theanine, the Main Amino Acid in Tea, Prevents Stress-Induced Brain Atrophy by Modifying Early Stress Responses2020

    • Author(s)
      Unno Keiko、Sumiyoshi Akira、Konishi Tomokazu、Hayashi Michiko、Taguchi Kyoko、Muguruma Yoshio、Inoue Koichi、Iguchi Kazuaki、Nonaka Hiroi、Kawashima Ryuta、Hasegawa-Ishii Sanae、Shimada Atsuyoshi、Nakamura Yoriyuki
    • Journal Title

      Nutrients

      Volume: 12 Issue: 1 Pages: 174-174

    • DOI

      10.3390/nu12010174

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential Effects of Nasal Inflammation and Odor Deprivation on Layer-Specific Degeneration of the Mouse Olfactory Bulb2020

    • Author(s)
      Hasegawa-Ishii Sanae、Imamura Fumiaki、Nagayama Shin、Murata Makiko、Shimada Atsuyoshi
    • Journal Title

      eneuro

      Volume: 7 Issue: 2 Pages: 0403-19

    • DOI

      10.1523/eneuro.0403-19.2020

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Physiological and pathological brain‐immune system interactions2020

    • Author(s)
      Shimada Atsuyoshi、Yokota Takanori
    • Journal Title

      Clinical and Experimental Neuroimmunology

      Volume: 11 Issue: 1 Pages: 3-4

    • DOI

      10.1111/cen3.12561

    • Related Report
      2019 Research-status Report
    • Open Access
  • [Journal Article] Principles of neuroanatomical architecture supporting brain-immune cell-cell interactions2020

    • Author(s)
      Shimada Atsuyoshi
    • Journal Title

      Clinical and Experimental Neuroimmunology

      Volume: 11 Issue: 1 Pages: 5-15

    • DOI

      10.1111/cen3.12559

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neuroinflammation and the blood-brain interface: New findings in brain pathology2020

    • Author(s)
      Kelley Keith W.、Shimada Atsuyoshi
    • Journal Title

      Clinical and Experimental Neuroimmunology

      Volume: 11 Issue: 1 Pages: 16-20

    • DOI

      10.1111/cen3.12558

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neuroplastic changes in the olfactory bulb associated with nasal inflammation in mice2019

    • Author(s)
      Hasegawa-Ishii Sanae、Shimada Atsuyoshi、Imamura Fumiaki
    • Journal Title

      Journal of Allergy and Clinical Immunology

      Volume: 143 Issue: 3 Pages: 978-989

    • DOI

      10.1016/j.jaci.2018.09.028

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Histological Architecture Underlying Brain-Immune Cell-Cell Interactions2019

    • Author(s)
      Shimada A
    • Organizer
      The 42nd Annual Meeting of the JNS Symposium ”Neuroinflammation and the Blood Brain Interface: New findings in brain pathology"
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Histological Architecture Underlying Brain-Immune Cell-Cell Interactions2019

    • Author(s)
      Shimada A
    • Organizer
      The 37th International Confernece of Australasian Winter Conference on Brain Research Symposia: Psychoneuroimmunology across the lifespan.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Acute responses of intracranial macrophages to LPS-induced systemic inflammation in newborn moice2019

    • Author(s)
      Shimada A, Miura A, Hasegawa-Ishii S
    • Organizer
      PsychoNeuroImmunology Research Society’s 26th Annual Scientific Meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Differential effects of nasal inflammation and odor deprivation on layer-specific degeneration of the olfactory bulb in mice2019

    • Author(s)
      Hasegawa-Ishii S, Imamura F, Shimada A
    • Organizer
      PsychoNeuroImmunology Research Society’s 26th Annual Scientific Meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Differential effects of nasal inflammation and odor deprivation on layer-specific degeneration of the olfactory bulb in mice (慢性鼻腔炎症と嗅覚遮断が嗅球の層特異的変性に及ぼす影響)2019

    • Author(s)
      Hasegawa-Ishii S, Imamura F, Shimada A
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Microglia and neuronal degeneration in senescence-accelerated mice2018

    • Author(s)
      Shimada A
    • Organizer
      19th International Congress of Neuropathology, Symposium 1 “Microglia and Synapses”, Tokyo, Sept, 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Cytokine-mediated cell-cell interaction between choroid plexus epithelium and stroma in response to systemic inflammation2018

    • Author(s)
      Shimada A, Miura A, Hasegawa-Ishii S
    • Organizer
      PsychoNeuroImmunology Research Society’s 25th Annual Scientific Meeting, Florida, USA, Jun 8, 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cytokine-mediated cell-cell interaction between choroid plexus epithelium and stroma in response to systemic inflammation (全身炎症に応答する脈絡叢上皮と間質のサイトカインを介した細胞間相互作用)2018

    • Author(s)
      Shimada A, Miura A, Hasegawa-Ishii S
    • Organizer
      第41回日本神経科学大会, 神戸, 2018.7.27
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Plastic changes in the olfactory bulb coupled with the inflammatory status of the nasal cavity (鼻腔炎症と寛解に伴う嗅球の可塑的変化)2018

    • Author(s)
      Hasegawa-Ishii S, Shimada A, Imamura F
    • Organizer
      第41回日本神経科学大会, 神戸, 2018.7.27
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] 杏林大学保健学部教員紹介

    • URL

      http://www.kyorin-u.ac.jp/univ/faculty/health/education/staff/detail.php?id=hea40288

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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