Meningeal immunity as a novel target for treating neurodevelopmental disorders induced by maternal immune activation

• Project/Area Number: 24650190
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: SHIMADA Atsuyoshi 愛知県心身障害者コロニー発達障害研究所, 病理学部, 室長 (50311444)
• Research Collaborator: ISHII Sanae , 日本学術振興会特別研究員RPD (40435863) ; INABA Muneo 関西医科大学, 医学部, 非常勤講師 (70115947)
• Project Period (FY): 2012 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 発達障害 / 炎症 / 免疫髄膜 / 脈絡叢自閉症 / 髄膜 / 脈絡叢 / サイトカイン / アストロサイト / 免疫

Research Abstract

Maternal inflammation during pregnancy is one of the risk factors for autism in offspring. In the present study using experimental animals, we showed that bone marrow-derived immune cells were stationed in the meningeal space that covered the brain parenchyma. The meningeal immunity played a key role to sense and react to peripheral inflammatory responses, resulting in the activation of brain parenchymal cells. Intracranial immune cells were located to the cephalic mesenchyme (meningeal precursors) during the fetal period, but not to the brain parenchyma. Therefore, we suggest that the effects of maternal inflammation on the fetal brains are induced by the reactions exerted by the cephalic mesenchymal immune cells during pregnancy.

Research Products

• [Journal Article] Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes (2013)
  • Author(s): Tanisawa K, Mikami E, Fuku N, Honda Y, Honda S, Ohsawa I, Ito M, Endo S, Ihara K, Ohno K, Kishimoto Y, Ishigami A, Maruyama N, Sawabe M, Iseki H, Okazaki Y, Hasegawa-Ishii S, Takei S, Shimada A, Hosokawa M, Mori M, Higuchi K, Takeda T, Higuchi M and Tanaka M
  • Journal Title: BMC Genomics Volume: 14 Pages: 248-248
  • NAID: 120007100717
• [Journal Article] Excitotoxicity-induced immediate surge in hippocampal prostanoid production has latent effects that promote chronic progressive neuronal death. (2013)
  • Author(s): Yoshikawa K., Kita Y., Furukawa A., Kawamura N., Hasegawa-Ishii S., Chiba Y., Takei S., Maruyama K., Shimizu T., Shimada A.
  • Journal Title: Prostaglandins Leukot Essent Fatty Acids. Volume: 88(5) Issue: 5 Pages: 373-381
  • DOI: 10.1016/j.plefa.2013.02.007
  • Peer Reviewed
• [Journal Article] Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus. (2012)
  • Author(s): Hasegawa-Ishii S, Shimada A, Inaba M, Li M, Shi M, Kawamura N, Takei S, Chiba Y, Hosokawa M, Ikehara S.
  • Journal Title: Brain Behav Immun. Volume: 29 Pages: 82-97
  • DOI: 10.1016/j.bbi.2012.12.010
  • Peer Reviewed
• [Journal Article] Immunohistochemical demonstration of increased prostaglandin F2α levels in the rat hippocampus following kainic acid-induced seizures (2012)
  • Author(s): Takei S, Hasegawa-Ishii S, Uekawa A, Chiba Y, Umegaki H, Hosokawa M, Woodward DF, Watanabe K and Shimada A
  • Journal Title: Neuroscience Volume: 218 Pages: 295-304
• [Journal Article] Immunohistochemical localization of aggresomal proteins in glial cytoplasmic inclusions in multiple system atrophy (2012)
  • Author(s): Chiba Y, Takei S, Kawamura N, Kawaguchi Y, Sasaki K, Hasegawa-Ishii S, Furukawa A, Hosokawa M and Shimada A
  • Journal Title: Neuropathology and Applied Neurobiology Volume: 38 Pages: 559-571
• [Journal Article] 脳と免疫系の相互作用という観点から老化促進モデルマウスをとらえる (2012)
  • Author(s): 島田厚良, 石井さなえ
  • Journal Title: 基礎老化研究 Volume: 36 Pages: 13-20
  • NAID: 10030253433
• [Journal Article] 脳と免疫系の相互作用という観点から老化促進モデルマウスをとらえる (2012)
  • Author(s): 島田厚良、石井さなえ
  • Journal Title: 基礎老化研究 Volume: 36(1) Pages: 13-20
  • NAID: 10030253433
  • Peer Reviewed
• [Journal Article] Immunohistochemical demonstration of increased prostaglandin F2alpha levels in the rat hippocampus following kainic acid-induced seizures (2012)
  • Author(s): Takei, S., Hasegawa-Ishii, S., Uekawa, A., Chiba, Y., Umegaki, H., Hosokawa, M., Woodward, D.F., Watanabe, K., and Shimada, A.
  • Journal Title: Neuroscience Volume: 218 Pages: 295-304
  • DOI: 10.1016/j.neuroscience.2012.05.013
  • Peer Reviewed
• [Journal Article] Immunohistochemical localization of aggresomal proteins in glial cytoplasmic inclusions in multiple system atrophy. (2012)
  • Author(s): Chiba Y., Takei S., Kawamura N., Kawaguchi Y., Sasaki K., Hasegawa-Ishii S., Furukawa A., Hosokawa M., Shimada A.
  • Journal Title: Neuropathol. Appl. Neurobiol. Volume: 38(6) Issue: 6 Pages: 559-71
  • DOI: 10.1111/j.1365-2990.2011.01229.x
  • Peer Reviewed
• [Journal Article] Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice (2012)
  • Author(s): Nobutaka Ohgami
  • Journal Title: Neurobiol Aging Volume: 33 Issue: 3 Pages: 626.e25-626.e34
  • DOI: 10.1016/j.neurobiolaging.2011.04.002
  • Peer Reviewed
• [Journal Article] Senescence-accelerated mice (SAMs) as a model for brain aging and immunosenescence (2011)
  • Author(s): Shimada A and Hasegawa-Ishii S
  • Journal Title: Aging Dis Volume: 2 Pages: 414-436
• [Journal Article] 免疫系と神経系の接点から老化促進モデルマウスをとらえる (2011)
  • Author(s): 島田厚良, 石井さなえ
  • Journal Title: 日本老年医学会雑誌 Volume: 48 Pages: 439-446
  • NAID: 10031130846
• [Presentation] Proteomic identification of oxidatively damaged proteins in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy (2014)
  • Author(s): Furukawa A, Kakita A, Chiba Y, Higuchi sY and Shimada A
  • Organizer: 17th Biennial Meeting of Society for Free Radical Research International
  • Place of Presentation: Kyoto
• [Presentation] Proteomic identification of oxidatively damaged proteins in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy (2014)
  • Author(s): Furukawa A, Kakita A, Chiba Y, Higuchi Y, Shimada A
  • Organizer: 17th Biennial Meeting of Society for Free Radical Research International
  • Place of Presentation: Kyoto International Conference Hall, Kyoto
• [Presentation] Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice (2013)
  • Author(s): Hasegawa-Ishii S and Shimada A
  • Organizer: Asian Association of Aging Research 2013 Seoul Symposium
  • Place of Presentation: Seoul
• [Presentation] 脳と免疫系のインターフェイスから SAMをとらえる (2013)
  • Author(s): 島田厚良
  • Organizer: 第28回老化促進モデルマウス(SAM)研究協議会
  • Place of Presentation: 名古屋
• [Presentation] Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus (2013)
  • Author(s): Hasegawa-Ishii S, Shimada A, Inaba M, Li M, Shi M, Takei S and Ikehara S
  • Organizer: PsychoNeuroImmunology Research Society's 20th Annual Scientific Meeting
  • Place of Presentation: Stockholm
• [Presentation] Immunohistochemical demonstration of enhanced prostaglandin F2alpha production following kainic acid-induced seizures in rat hippocampus (2013)
  • Author(s): Takei S, Hasegawa-Ishii S, Woodward DF, Watanabe K and Shimada A
  • Organizer: PsychoNeuroImmunology Research Society's 20th Annual Scientific Meeting
  • Place of Presentation: Stockholm
• [Presentation] 脳と免疫系の接点としての脈絡叢間質および付着部における細胞動態とサイトカイン発現 (2013)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、細川昌則、池原進
  • Organizer: 第54回日本神経病理学会総会
  • Place of Presentation: 東京
• [Presentation] Immunohistochemical demonstration of enhanced prostaglandin F2alpha production following kainic acid-induced seizures in rat hippocampus (2013)
  • Author(s): Takei S, Hasegawa-Ishii S, Woodward DF, Watanabe K and Shimada A
  • Organizer: PsychoNeuroImmunology Research Society’s 20th Annual Scientific Meeting
  • Place of Presentation: Raddison Blu Royal Park Hotel, SE-169 03 Solna, Stockholm, Sweden
• [Presentation] Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus (2013)
  • Author(s): Hasegawa-Ishii S, Shimada A, Inaba M, Li M, Shi M, Takei S and Ikehara S
  • Organizer: PsychoNeuroImmunology Research Society’s 20th Annual Scientific Meeting
  • Place of Presentation: Raddison Blu Royal Park Hotel, SE-169 03 Solna, Stockholm, Sweden
• [Presentation] Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice (2013)
  • Author(s): Hasegawa-Ishii S and Shimada A
  • Organizer: Asian Association of Aging Research 2013 Seoul Symposium
  • Place of Presentation: International Conference Hall, University of Seoul, Seoul, Korea
  • Invited
• [Presentation] 脳と免疫系の接点としての脈絡叢間質および付着部における細胞動態とサイトカイン発現 (2013)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、細川昌則、池原 進
  • Organizer: 第５４回日本神経病理学会総会
  • Place of Presentation: タワーホール船堀、東京
• [Presentation] 脳と免疫系のインターフェイスからSAMをとらえる (2013)
  • Author(s): 島田厚良
  • Organizer: 第28回老化促進モデルマウス(SAM)研究協議会
  • Place of Presentation: 愛知学院大学 歯学・薬学図書館情報センター、名古屋市
  • Invited
• [Presentation] 老化促進モデルマウスにみられる骨髄由来細胞の脳実質へのリクルートの亢進 (2012)
  • Author(s): 島田厚良、石井さなえ、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] 骨髄由来免疫系細胞が健常脳に進入する新たな経路 : 骨髄内骨髄移植による組織学的同定 (2012)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] Intra bone marrow procedure facilitates entry of transplanted bone marrow cells through the tenia of choroid plexus into brain parenchyma (2012)
  • Author(s): Hasegawa-Ishii S, Shimada A, Inaba M, Li M, Shi M, Kawamura N, Takei S and Ikehara S
  • Organizer: PsychoNeuroImmunology Research Society's 19th Annual Scientific Meeting
  • Place of Presentation: San Diego
• [Presentation] Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice (2012)
  • Author(s): Shimada A, Hasegawa-Ishii S, Inaba M, Li M, Shi M, Kawamura N, Takei S and Ikehara S
  • Organizer: PsychoNeuroImmunology Research Society's 19th Annual Scientific Meeting
  • Place of Presentation: San Diego
• [Presentation] 骨髄由来免疫系細胞が健常脳に進入する新たな経路の骨髄内骨髄移植による組織学的同定 (2012)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] 骨髄由来免疫系細胞が健常脳に進入する新たな経路の骨髄内骨髄移植による組織学的同定 (2012)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 京王プラザホテル（東京）
• [Presentation] Intra-bone marrow procedure facilitates entry of transplanted bone marrow cells through the tenia of choroid plexus into brain parenchyma (2012)
  • Author(s): Sanae Hasegawa-Ishii, Atsuyoshi Shimada, Muneo Inaba, Ming Li, Ming Shi, Noriko Kawamura, Shiro Takei, Susumu Ikehara
  • Organizer: PsychoNeuroImmunology Research Society’s 19th Annual Scientific Meeting
  • Place of Presentation: Manchester Grand Hyatt San Diego (San Diego, CA, USA)
• [Presentation] 骨髄由来免疫系細胞が健常脳に進入する新たな経路：骨髄内骨髄移植による組織学的同定 (2012)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第53回日本神経病理学会総会
  • Place of Presentation: 朱鷺メッセ（新潟市）
• [Presentation] 老化促進モデルマウスにみられる骨髄由来細胞の脳実質へのリクルートの亢進 (2012)
  • Author(s): 島田厚良、石井さなえ、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第53回日本神経病理学会総会
  • Place of Presentation: 朱鷺メッセ（新潟市）
• [Presentation] 重症心身障害者にみる白質傷害の病理
  • Author(s): 島田厚良
  • Organizer: 日本小児病理研究会 第９回小児病理セミナー”発達期神経疾患の臨床と病理”
  • Place of Presentation: 大阪市立総合医療センター（大阪市）
  • Invited
• [Book] SAMP10 strain as a model for the study of brain aging, In "The senescence-accelerated mouse (SAM): Achievements and Future Directions" (Ed.) Takeda T, Akiguchi I, Higuchi K, Hosokawa M, Hosokawa T and Nomura Y (2013)
  • Author(s): Shimada A, Hasegawa-Ishii S and Furukawa A
  • Publisher: Elsevier, Amsterdam
• [Book] SAMP10 strain as a model for the study of brain aging, In: “The senescence-accelerated mouse (SAM): Achievements and Future Directions” (2013)
  • Author(s): Shimada A, Hasegawa-Ishii S and Furukawa A
  • Total Pages: 18
  • Publisher: Elsevier, Amsterdam
• [Book] SAMP10 strain as a model for the study of brain aging, In: T. Takeda, ed. The senescence-accelerated mouse (SAM): Achievements and Future Directions (2013)
  • Author(s): A. Shimada, A., Hasegawa-Ishii, S., and Furukawa, A.
  • Total Pages: 17
  • Publisher: Elsevier