Non-infectious neuroinflammatory response by glia: general mechanism of neurodegenerative diseases

• Project/Area Number: 18K05999
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42020:Veterinary medical science-related
• Research Institution: Osaka Prefecture University
• Principal Investigator: Nakamura Yoichi 大阪府立大学, 生命環境科学研究科, 客員研究員 (90180413)
• Co-Investigator(Kenkyū-buntansha): 森山 光章 大阪府立大学, 生命環境科学研究科, 教授 (20275283) ; 高野 桂 大阪府立大学, 生命環境科学研究科, 准教授 (50453139)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ミクログリア / アストロサイト / 非感染性神経炎症 / 亜鉛イオン / エクオール / 短中鎖脂肪酸 / インスリン / リゾリン脂質 / リゾフォスファチジルセリン / リゾフォスファチジルイノシトール / 神経炎症 / 短鎖脂肪酸 / 中鎖脂肪酸 / Zn2+ / 神経炎症反応 / 神経変性疾患

Outline of Final Research Achievements

We found several factors which regulated the cell functions using astrocyte and microglial cell cultures as a model of the neuroinflammatory reaction. Zinc ion (Zn2+) and short/middle chain fatty acids (C2,4/C6-C12) enhanced astrocyte inflammation, on the contrary, S-equol (an isoflavone) suppress the inflammation. We also found that astrocytes express and release insulin, and that inflammation reaction depressed the expression. Interestingly, in microglia, the short/middle chain fatty acids cause suppression of the inflammation. In addition, the lysophospholipid (lysophosphatidylinositol and lysophosphatidylserine) also lead to suppression of the microglial inflammatory reaction.

Academic Significance and Societal Importance of the Research Achievements

虚血神経細胞障害やアルツハイマー病をはじめとする各種神経変性疾患においては，細菌性感染や白血球浸潤がない状況下でも，グリア細胞を主役とする神経炎症反応が起こって病態が増悪していると考えられる。新型コロナ感染症の後遺症としての神経障害も脳内のグリア細胞による神経炎症反応が原因となっている可能性が高い。今回見出されたいくつかの因子の作用機構や標的をさらに検討することにより，治療薬が創出されることにつながることが期待される。
短中鎖脂肪酸がアストロサイトの炎症反応を増強しミクログリアのそれを反対に抑制したことは両グリア細胞の相補的な新たな役割を示すものであり学術的意義が高い。

Research Products

• [Journal Article] Acetate suppresses lipopolysaccharide-stimulated nitric oxide production in primary rat microglia but not in BV-2 microglia cells. (2021)
  • Author(s): Moriyama M, Nishimura Y, Kurebayashi R, Minamihata T, Kawabe K, Takano K, Nakamura Y.
  • Journal Title: Current Molecular Pharmacology Volume: Epub Pages: 253-260
  • DOI: 10.2174/1874467213666200420101048
  • Peer Reviewed / Open Access
• [Journal Article] Lysophosphatidylinositol, an endogenous ligand for G protein-coupled receptor 55, has anti-inflammatory effects in cultured microglia. (2020)
  • Author(s): Minamihata T, Moriyama M, Takano K, Nakamura Y.
  • Journal Title: Inflammation Volume: 43 Pages: 1971-1987
  • DOI: 10.1007/s10753-020-01271-4
  • Peer Reviewed / Open Access
• [Journal Article] Acetate attenuates the astrocyte swelling and brain edema in severe liver failure. (2020)
  • Author(s): Moriyama M, Minamihata T, Jayakumar AR, Norenberg MD
  • Journal Title: American Journal of Gastroenterology Volume: 114
  • DOI: 10.14309/ajg.0000000000000372
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pivotal role of inter-organ aspartate metabolism for treatment of mitochondrial aspartate-glutamate carrier 2 (citrin) deficiency, based on the mouse model. (2019)
  • Author(s): Saheki T, Moriyama M, Kuroda E, Funahashi A, Yasuda I, Setogawa Y, Gao Q, Ushikai M, Furuie S, Yamamura KI, Takano K, Nakamura Y, Eto K, Kadowaki T, Sinasac DS, Furukawa T, Horiuchi M, Tai YH.
  • Journal Title: Sci. Rep. Volume: 9 (1) Pages: 4179-4179
  • DOI: 10.1038/s41598-019-39627-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglia endocytose amyloid-beta through the binding of transglutaminase 2 and milk fat globule EGF factor 8 protein (MFG-E8). (2018)
  • Author(s): Kenji Kawabe, Katsura Takano, Mitsuaki Moriyama, Yoichi Nakamura.
  • Journal Title: Neurochemical Research, Volume: 43 Pages: 32-40
  • DOI: 10.1007/s11064-017-2284-y
  • Peer Reviewed
• [Journal Article] Inhibition of Gap Junction Elevates Glutamate Uptake in Cultured Astrocytes. (2018)
  • Author(s): Katsura Takano, Masato Ogawa, Kenji Kawabe, Mitsuaki Moriyama, Yoichi Nakamura.
  • Journal Title: Neurochemical Research Volume: 43 Pages: 50-56
  • DOI: 10.1007/s11064-017-2316-7
  • Peer Reviewed
• [Journal Article] Zinc potentiates lipopolysaccharide-induced nitric oxide production in cultured primary rat astrocytes. (2018)
  • Author(s): Moriyama M, Fujitsuka S, Kawabe K, Takano K, Nakamura Y.
  • Journal Title: Neurochemical Research Volume: 43 Pages: 363-374
  • DOI: 10.1007/s11064-017-2431-5
  • Peer Reviewed
• [Journal Article] A dibenzoylmethane derivative inhibits lipopolysaccharide-induced NO production in mouse microglial cell line BV-2. (2018)
  • Author(s): Takano K, Ishida N, Kawabe K, Moriyama M, Hibino S, Choshi T, Hori O, Nakamura Y.
  • Journal Title: Neurochemistry International Volume: 印刷中 Pages: 126-131
  • DOI: 10.1016/j.neuint.2017.04.002
  • NAID: 120007018399
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Insulin expression in cultured astrocytes and the decrease by amyloid β. (2018)
  • Author(s): Katsura Takano, Keisuke Koarashi, Kenji Kawabe, Masanori Itakura, Hidemitsu Nakajima, Mitsuaki Moriyama, Yoichi Nakamura.
  • Journal Title: Neurochemistry International Volume: 印刷中 Pages: 171-177
  • DOI: 10.1016/j.neuint.2017.10.017
  • Peer Reviewed
• [Journal Article] S-Equol, a major isoflavone from soybean, inhibits nitric oxide production in lipopolysaccharide-stimulated rat astrocytes partially via the GPR30-mediated pathway. (2018)
  • Author(s): Moriyama M, Hashimoto A, Satoh H, Kawabe K, Ogawa M, Takano K, Nakamura Y.
  • Journal Title: International Journal of Inflammation Volume: - Pages: 8496973-8496973
  • DOI: 10.1155/2018/8496973
  • Peer Reviewed / Open Access
• [Presentation] ミクログリア炎症反応に対するLysophosphatidylinositolの抑制効果 (2020)
  • Author(s): 南畑 朋輝，森山 光章，高野 桂，中村 洋一
  • Organizer: 第63回日本神経化学会大会
• [Presentation] Medium-chain fatty acids attenuate neuroinflammatory responses by activated microglia (2019)
  • Author(s): Y. Nakamura, Y. Nishimura, K. Takano, M. Moriyama
  • Organizer: XIV Europian Meeting on Glial cells: Porto/ Portugal
  • Int'l Joint Research
• [Presentation] Butyrate augments nitric oxide production in lipopolysaccharide-stimulated rat astrocytes (2019)
  • Author(s): Moriyama M, Satoh H, Takano K, Nakamura Y.
  • Organizer: Neuro2019, Niigata, 7/25-7/28
  • Int'l Joint Research