Why does sleep disorder cause diseases?

• Project/Area Number: 15K15147
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Hokkaido University
• Principal Investigator: Murakami Masaaki 北海道大学, 遺伝子病制御研究所, 教授 (00250514)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 炎症 / ストレス / 神経 / ゲートウェイ反射 / 炎症回路 / 睡眠障害 / 神経活性化 / 睡眠障害ストレス

Outline of Final Research Achievements

The central nervous system (CNS) equips the blood-brain barrier (BBB) to limit exchanges of substances. However, immune-cell infiltration occurs in CNS. We have identified the dorsal vessels of the fifth lumbar (L5) spinal cord as a gateway for immune cells to CNS, which is critical for neuro-inflammation development. In this proposal, how stress-mediated neural activations affect the gateway was examined. I found that specific nerve activations by sleep disorder completely change the gateway site from L5 to the brain, followed by sudden death by gastrointestinal bleeding. This “stress-gateway reflex” explains a classical proverb “Illness starts in the mind.”, which we generally experience but the mechanisms are not well known. By continuing the gateway reflex research, it can be expected that manipulations of local neural activations will be a new therapeutic approach for certain diseases.

Research Products

• [Journal Article] Recent advances in neuroimmune interactions. (2017)
  • Author(s): Murakami, M.
  • Journal Title: Clin Exp Neuroimmunol. Volume: 8 Issue: 1 Pages: 3-4
  • DOI: 10.1111/cen3.12382
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gateway reflex, a new paradigm of neuro-immune interaction (2017)
  • Author(s): Ohki, T., D. Kamimura, Y. Arima, M. Murakami.
  • Journal Title: Clin Exp Neuroimmunol. Volume: 8 Issue: 1 Pages: 23-32
  • DOI: 10.1111/cen3.12378
  • NAID: 40021263574
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gateway reflexes are stimulated by neural activations and promote the pathogenesis of multiple sclerosis models. (2017)
  • Author(s): Higuchi, K., D. Kamimura, A. Stofkova, N. Nishikawa, T. Ohki, Y. Arima, M. Murakami.
  • Journal Title: Nutrition and Lifestyle in Neurological Autoimmune Diseases. Volume: Chapter 5 Pages: 39-45
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Breakpoint cluster region-mediated inflammation is dependent on casein kinase II. (2016)
  • Author(s): Meng, J., J-J Jiang, T. Atsumi, H. Bando, Y. Okuyama, L. Sabharwal, I. Nakagawa, H. Higuchi, M. Ota, M. Okawara, R. Ishitani, O. Nureki, D. Higo, Y. Arima, H. Ogura, D. Kamimura and M. Murakami.
  • Journal Title: J Immunol. Volume: 197(8) Issue: 8 Pages: 3111-3119
  • DOI: 10.4049/jimmunol.1601082
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Control of chronic inflammation by the inflammation amplifier and gateway reflexes. (2016)
  • Author(s): Ota, M., D. Kamimura, I. Nakagawa, H. Higuchi, Y. Tanaka, M. Fujita, S. Hiratsuka, M. Okawara, K. Murakami, T. Atsumi, Y. Arima and M. Murakami.
  • Journal Title: Advances in Medicine and Biology. Volume: 104: Chapter 4 Pages: 65-86
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells. (2016)
  • Author(s): Kamimura, D. Y. Arima, M. Tsuruoka, J-J Jiang, H. Bando, J. Meng, L. Sabharwal, A. Stofkova, N. Nishikawa, K. Higuchi, H. Ogura, T. Atsumi, M. Murakami.
  • Journal Title: Int Immunol. Volume: 28(3) Issue: 3 Pages: 117-126
  • DOI: 10.1093/intimm/dxv059
  • NAID: 120005851045
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of inflammation amplifier-induced growth factor expression in the development of inflammatory diseases. (2015)
  • Author(s): Nakagawa, I., D. Kamimura, T. Atsumi, Y. Arima, M. Murakami.
  • Journal Title: Crit Rev Immunol. Volume: 35(5) Pages: 365-78
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Naive T cell homeostasis regulated by stress responses and TCR signaling. (2015)
  • Author(s): Kamimura, D., T. Atsumi, A. Stofkova, N. Nishikawa, T. Ohki, H. Suzuki, K. Katsunuma, J-J Jiang, H. Bando, J. Meng, L. Sabharwal, H. Ogura, T. Hirano, Y. Arima, M. Murakami.
  • Journal Title: Front Immunol Volume: 6
  • DOI: 10.3389/fimmu.2015.00638
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Klotho-related molecules upregulated by smoking habit in apparently healthy men: A crosssectional study. (2015)
  • Author(s): Nakanishi, K., M. Nishida1, M. Harada, T. Ohama, N. Kawada, M. Murakami, T. Moriyama1, K. Yamauchi-Takihara.
  • Journal Title: Sci Rep. Volume: 5 Pages: 14230-14230
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pain is an inducer for relapse in multiple sclerosis models via a regional neural signal. (2015)
  • Author(s): Arima, Y., K. Higuchi, N. Nishikawa, A. Stofkova, T Ohki, D. Kamimura, M. Murakami.
  • Journal Title: Clin Exp Neuroimmunol. Volume: 6 Issue: 4 Pages: 343-344
  • DOI: 10.1111/cen3.12250
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model (2015)
  • Author(s): Arima, Y., D. Kamimura, T. Atsumi, M. Harada, T. Kawamoto, N. Nishikawa, A. Stofkova1, T. Ohki, K. Higuchi, Y. Morimoto, P. Wieghofer, Y. Okada, Y. Mori, S. Sakoda, S. Saika, Y. Yoshioka, I. Komuro, T. Yamashita, T. Hirano, M. Prinz, M. Murakami.
  • Journal Title: eLife Volume: 4 Pages: 1-23
  • DOI: 10.7554/elife.08733
  • NAID: 120005757989
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of T cell- glial cell interactions in creating and amplifying Central Nervous System inflammation and Multiple Sclerosis disease symptoms. (2015)
  • Author(s): Huseby, ES., D. Kamimura, Y. Arima, CS. Parello, K. Sasaki, M. Murakami.
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 9
  • DOI: 10.3389/fncel.2015.00295
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] mTOR complex signaling through the SEMA4A-Plexin B2 axis is required for optimal activation and differentiation of CD8+ T cells. (2015)
  • Author(s): Ito, D., S. Nojima, M. Nishide, T. Okuno, H. Takamatsu, S. Kang, T. Kimura, Y. Yoshida, K. Morimoto, Y. Maeda, T. Hosokawa, T. Toyofuku, J. Ohshima, D. Kamimura, M. Yamamoto, M. Murakami, E. Morii, H. Rakugi, Y. Isaka, A. Kumanogoh.
  • Journal Title: J Immunol. Volume: 195(3) Pages: 934-43
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. (2015)
  • Author(s): Hashimoto-Kataoka, T., N. Hosen, T. Sonobe, Y. Arita, T. Yasui, T. Masaki, M. Minami, T. Inagaki, S. Miyagawa, Y. Sawa, M. Murakami, A. Kumanogoh, K. Yamauchi-Takihara, M. Okumura, T. Kishimoto, I. Komuro, M. Shirai, Y. Sakata, Y. Nakaoka.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 112(20)
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR. (2015)
  • Author(s): Kamimura, D., K. Katsunuma, Y. Arima, T. Atsumi, J-J Jiang, H. Bando, J. Meng, L. Sabharwal, A. Stofkova, N. Nishikawa, H. Suzuki, H. Ogura, N. Ueda, M. Tsuruoka, M. Harada, J. Kobayashi, T. Hasegawa, H. Yoshida, H. Koseki, I. Miura, S. Wakana, K. Nishida, H. Kitamura, T. Fukada, T. Hirano, and M. Murakami
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 7474-7474
  • DOI: 10.1038/ncomms8474
  • NAID: 120005647268
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CD147/Basigin limits lupus nephritis and TH17 cell differentiation by inhibiting the IL-6/STAT3 pathway. (2015)
  • Author(s): Maeda, K., T. Kosugi, W. Sato, H. Kojima, Y. Sato, D. Kamimura, N. Kato, N. Tsuboi, Y. Yuzawa, S. Matsuo, M. Murakami, S. Maruyama, K. Kadomatsu.
  • Journal Title: Arthritis Rheumatol. Volume: 67(8) Pages: 2185-2195
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immune Cell Gateways in the CNS Regulated by Regional Neural Stimulations. (2015)
  • Author(s): Kamimura, D., A. Stofkova, N. Nishikawa, T. Atsumi, Y. Arima, M. Murakami.
  • Journal Title: Clin Exp Neuroimmunol. Volume: 6(2) Pages: 120-128
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 炎症回路とゲートウェイ反射による病態の制御 (2017)
  • Author(s): 村上正晃
  • Organizer: 第1回Fibrosis
  • Place of Presentation: TKPガーデンシティPREMIUM名古屋駅前、名古屋市、愛知県
  • Invited
• [Presentation] サイトカインと神経活性化による慢性炎症の誘導機構 (2016)
  • Author(s): 村上正晃
  • Organizer: 北大・部局横断シンポジウム
  • Place of Presentation: 北海道大学 (北海道、札幌市)
  • Year and Date: 2016-03-07
  • Invited
• [Presentation] 神経による炎症の制御 －多発性硬化症モデルからわること- (2016)
  • Author(s): 村上正晃
  • Organizer: 日本神経学会北海道地方会
  • Place of Presentation: 北海道大学 (北海道、札幌市)
  • Year and Date: 2016-03-06
  • Invited
• [Presentation] 反応性関節炎における炎症回路の関与 (2016)
  • Author(s): 村上正晃
  • Organizer: インド-日本SICPシンポジウム
  • Place of Presentation: 日本医療研究開発機構 (東京都、千代田区)
  • Year and Date: 2016-02-25
  • Int'l Joint Research / Invited
• [Presentation] Kdelr1-PP1系のT細胞のストレス解消への役割 (2016)
  • Author(s): 村上正晃
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター、仙台市、宮城県
  • Invited
• [Presentation] ゲートウェイ反射 による神経炎症の惹起機構 (2016)
  • Author(s): 村上正晃
  • Organizer: 第1回Japanese School of Neuroimmunologyシンポジウム
  • Place of Presentation: 東京医科歯科大学、文京区、東京都
  • Invited
• [Presentation] ゲートウェイ反射、感覚神経の活性化を起点とする炎症誘導機構 (2016)
  • Author(s): 村上正晃
  • Organizer: 第20回日本神経麻酔集中治療学会
  • Place of Presentation: 北海道大学学術交流会館、札幌市、北海道
  • Invited
• [Presentation] 末梢神経を起点とする炎症の制御機構、ゲートウェイ反射 (2016)
  • Author(s): 村上正晃
  • Organizer: 第39回末梢神経を語る会
  • Place of Presentation: 広島国際会議場、広島市、広島県
  • Invited
• [Presentation] ゲートウェイ反射、局所の交感神経活性化を起点とする炎症誘導機構御 (2016)
  • Author(s): 村上正晃
  • Organizer: 日本リウマチ学会第3回ベーシックリサーチカンファレンス
  • Place of Presentation: アキバプラザ、千代田区、東京都
  • Invited
• [Presentation] ゲートウェイ反射、新しい神経-炎症のクロストーク (2015)
  • Author(s): 村上正晃
  • Organizer: 遺伝子病制御研究所共同利用共同研究集会「感染・免疫・炎症・発癌」
  • Place of Presentation: 北海道大学 (北海道、札幌市)
  • Year and Date: 2015-12-18
  • Invited
• [Presentation] 炎症回路はゲートウェイ反射の分子基盤である (2015)
  • Author(s): 村上正晃
  • Organizer: Advans研究会
  • Place of Presentation: ホテルグランドパレス (東京都、千代田区)
  • Year and Date: 2015-12-12
  • Invited
• [Presentation] ゲートウェイ反射による中枢神経系炎症の制御 (2015)
  • Author(s): 村上正晃
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートピアホテル (兵庫県、神戸市)
  • Year and Date: 2015-12-02
  • Invited
• [Presentation] Pain sensation induces relapse via the gateway reflex in EAE, a MS model (2015)
  • Author(s): 村上正晃
  • Organizer: 日本免疫学会シンポジウム
  • Place of Presentation: 札幌コンベンションセンター (北海道、札幌市)
  • Year and Date: 2015-11-19
  • Invited
• [Presentation] ゲートウェイ反射による認知症を含む中枢神経系疾患の治療の可能性 (2015)
  • Author(s): 村上正晃
  • Organizer: 第34回日本認知症学会総会
  • Place of Presentation: リンクステーションホール青森 (青森県、青森市)
  • Year and Date: 2015-10-03
  • Invited
• [Presentation] 炎症回路による慢性炎症疾患の制御 (2015)
  • Author(s): 村上正晃
  • Organizer: IL6の臨床と基礎を結ぶ会
  • Place of Presentation: 北海道大学 (北海道、札幌市)
  • Year and Date: 2015-09-14
  • Invited
• [Presentation] ゲートウェイ反射による脊髄再生の可能性 (2015)
  • Author(s): 村上正晃
  • Organizer: Walk Again 2015 in 札幌―脊髄再生シンポジウム
  • Place of Presentation: 北海道大学 (北海道、札幌市)
  • Year and Date: 2015-09-05
  • Invited
• [Presentation] ゲートウェイ反射を介する神経疾患の制御機構 (2015)
  • Author(s): 村上正晃
  • Organizer: 第3回鹿児島免疫性神経疾患研究会
  • Place of Presentation: レンブラントホテル鹿児島 (鹿児島県、鹿児島市)
  • Year and Date: 2015-08-25
  • Invited
• [Presentation] 神経刺激を介する病態の制御機構 (2015)
  • Author(s): 村上正晃
  • Organizer: 研究所ネットワーク国際シンポジウム
  • Place of Presentation: 北海道大学 (北海道、札幌市)
  • Year and Date: 2015-07-23
  • Invited
• [Presentation] 炎症回路による慢性炎症の制御 (2015)
  • Author(s): 村上正晃
  • Organizer: 日本動脈硬化学会
  • Place of Presentation: 仙台国際センター (宮城県、仙台市)
  • Year and Date: 2015-07-09
  • Invited
• [Presentation] 神経反射刺激を介する病態の制御機構 (2015)
  • Author(s): 村上正晃
  • Organizer: 非感染性疾患の病態解明と診断・治療法の開発拠点の形成
  • Place of Presentation: 自治医科大学 (栃木県、下野市)
  • Year and Date: 2015-07-06
  • Invited
• [Presentation] 中枢神経系の慢性炎症とゲートウェイ反射 (2015)
  • Author(s): 村上正晃
  • Organizer: NCNP神経免疫国際シンポジウム
  • Place of Presentation: 国立精神・神経医療研究センター (東京都、小平市)
  • Year and Date: 2015-06-10
  • Invited
• [Book] Multiple Sclerosis (2015)
  • Author(s): Kamimura, D., Y. Arima, T. Atsumi, J. Meng, L. Sabharwal, H. Bando, J-J. Jiang, ES. Huseby, M. Murakami.
  • Total Pages: 538
  • Publisher: Elsevier
• [Remarks] 痛みが神経の病気を悪化させることを実証
  • URL: http://www.igm.hokudai.ac.jp/neuroimmune/jpn/research/10-Pain-eLife.html
• [Remarks] Tリンパ球がストレスを解消する機構を解明