Investigation of inflammation mechanisms via the stress-mediated endothelial cell activation

• Project/Area Number: 15K19122
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Hokkaido University
• Principal Investigator: Arima Yasunobu 北海道大学, 遺伝子病制御研究所, 助教 (70724748)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ゲートウェイ反射 / 炎症 / ストレス / 神経活性化 / 疼痛ストレス

Outline of Final Research Achievements

In this research, we focused on the local inflammation induction mechanism which is induced by regional neural activation "gateway reflex" and analyzed how nerve activation by pain or stress influences the inflammatory pathology. Firstly, pain stimulus activates the sympathetic nerve innervated to the ventral vessels in spinal cord through the anterior cingulate cortex, followed by increment of chemokine expression from activated monocytes and endothelial cells and induction of acummulation of immune cells for relapse of disease. Furthermore, excessive stress caused by sleep disorder induces inflammation in the brain, and revealed that these inflammations eventually induce lethal gastrointesitnal failure by activating new neural circuits. These results explain the molecular mechanism of "disease is mind" and can be expected to be applied to new treatment methods.

Research Products

• [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
  • DOI: 10.1016/b978-0-12-805298-3.00005-0
  • ISBN: 9780128052983
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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] 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] 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] 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] 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] 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] 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: 印刷中 Issue: 2 Pages: 120-128
  • DOI: 10.1111/cen3.12198
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A Pain-mediated Neural Signal Induces Relapse in An Experimental Autoimmune Encephalomyelitis. (2016)
  • Author(s): Yasunobu Arima
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター、宜野湾市、沖縄県
  • Year and Date: 2016-12-05
• [Presentation] 痛み刺激による感覚-交感神経活性化を介した 多発性硬化症モデルEAEの再発機構の解析 (2016)
  • Author(s): 有馬康伸
  • Organizer: 第28回日本神経免疫学会学術集会
  • Place of Presentation: 長崎ブリックホール、長崎市、長崎県
  • Year and Date: 2016-09-29
• [Presentation] 痛み刺激は感覚神経-交感神経の活性化を介して 多発性硬化症モデルの病態を再発させる (2016)
  • Author(s): 有馬康伸
  • Organizer: 第89回日本生化学大会
  • Place of Presentation: 東北大学、仙台市、宮城県
  • Year and Date: 2016-09-25
• [Presentation] Pain is an inducer for relapse in multiple sclerosis models via the sensory-sympathetic nerve activation (2016)
  • Author(s): Yasunobu Arima
  • Organizer: International Congress of Immunology 2016
  • Place of Presentation: Merborne, Australia
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] 痛み刺激は感覚-交感神経活性化を介して多発性硬化症モデルEAEの再発を誘導する (2016)
  • Author(s): 有馬康伸
  • Organizer: 第81回日本インターフェロンサイトカイン学会学術集会
  • Place of Presentation: 長崎大学、長崎市、長崎県
  • Year and Date: 2016-05-13
• [Presentation] Pain is an inducer for relapse in multiple sclerosis models via the sensory-sympathetic nerve activation. (2016)
  • Author(s): 有馬康伸
  • Organizer: Stromal Cells in Immunity
  • Place of Presentation: keystone (Colorado, US)
  • Year and Date: 2016-02-07
  • Int'l Joint Research
• [Presentation] 痛み刺激による感覚-交感神経活性化を介した多発性硬化症モデルEAEの再発機構の解明 (2016)
  • Author(s): 有馬康伸
  • Organizer: 第53回日本生化学会北海道支部例会
  • Place of Presentation: 北海道大学鈴木章ホール、札幌市、北海道
• [Presentation] 痛み刺激による感覚-交感神経活性化を介した多発性硬化症モデルEAEの再発機構の解析 (2016)
  • Author(s): 有馬康伸
  • Organizer: 第49回北海道病理談話会
  • Place of Presentation: 北海道大学医学部学友会館フラテ、札幌市、北海道
• [Presentation] 痛み刺激は感覚-交感神経活性化を介して多発性硬化症モデルEAEの再発を誘導する (2015)
  • Author(s): 有馬康伸
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド (兵庫県、神戸市)
  • Year and Date: 2015-12-01
• [Presentation] A Cellular Metabolite in An Inflammation Site Regulates The Pathological Condition of Experimental Autoimmune Encephalomyelitis. (2015)
  • Author(s): 有馬康伸
  • Organizer: 日本免疫学会学術集会
  • 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: 2015-11-18
• [Presentation] 神経刺激による炎症制御機構の解明 (2015)
  • Author(s): 有馬康伸
  • Organizer: 第2回JCRベーシックリサーチカンファレンス
  • Place of Presentation: 東京大学 (東京都、文京区)
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] Regional Neural Activation Influences Immune Signals in The Central Nervous System via The Inflammation Amplifier Activation (2015)
  • Author(s): 有馬康伸
  • Organizer: UCL Molecular Cell Biology Symposium 2015
  • Place of Presentation: Senate House (London, UK)
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [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.
  • 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