Title of Presentation

“The Development of Tissue-Specific Inflammatory Diseases by the Gateway Reflex”

Recent studies have found how our immune system and central nervous system are mutually linked at the molecular level. In 2012, we discovered one such linkage, the gateway reflex. The gravity gateway reflex is a series of events in which gravity-specific neural circuit activation causes the formation of a breaching point for myelin-autoreactive CD4+ T cells (i.e. blood vessel gateway) in the dorsal vessels of the fifth lumber spinal cord, resulting in the development of tissue-specific inflammatory diseases. An analysis of the molecular mechanisms responsible for this phenomenon revealed that sensory-sympathetic crosstalk from the soleus muscles, which are the main anti-gravity muscles, leads to the formation of a blood vessel gateway at the site in a noradrenaline-dependent manner. Based on these discoveries, we sent pathological model mice to the International Space Station in 2019 for joint research with JAXA and NASA to analyze the mechanisms of controlling the gateway reflex in zero gravity.

Besides gravity, other types of gateway reflexes depending on different stimuli have since been identified, including pain, stress, light, remote inflammation, and artificial electrical stimulation. Regardless of the stimulation, all cause the formation of blood vessel gateways to either induce or suppress tissue-specific inflammation in the presence of autoreactive CD4+ T cells in the blood. The stress gateway reflex, in particular, has been found to cause the following chain of events. When myelin-autoreactive CD4+ T cells accumulate to a certain quantity in the blood, the gateway reflex occurs in two specific vessels in the brain, inducing microinflammation. Then, ATP is produced at the sites of the brain microinflammation, where it acts as a neurotransmitter to activate a new neural circuit. Ultimately, the vagus nerve, which innervates the upper gastrointestinal tract, is hyper-activated, eventually causing inflammation in the stomach and duodenum, heart failure, and finally sudden death. In this presentation, I will give an overview of the discovery of the gravity gateway reflex and the development that followed, and also want to discuss the possibility of developing new treatments based on neural modulation using the gateway reflex, which are currently being studied in our moonshot project.

Profile

Web Site URL

http://www.igm.hokudai.ac.jp/neuroimmune/Eindex.html

A brief Biography(As of August 1 2021)

Mar 1989	Faculty of Veterinary Medicine, Hokkaido University
Mar 1993	Ph.D., Graduate School of Medicine, Osaka University
Apr 1993	Research assistant, Institute of Immunological Science, Hokkaido University
Apr 2000	Postdoctoral fellow, Howard Hughes Medical Institute, National Jewish Medical and Research Center (Overseas Research Fellowship, The Japan Society for the Promotion of Science)
Apr 2002	Associate Professor, The University of Colorado
Apr 2003	Assistant Professor, Graduate School of Medicine, Osaka University
Apr 2007	Associate Professor, Graduate School of Frontier Biosciences, Osaka University
Apr 2014-Present	Professor, Institute for Genetic Medicine / Graduate School of Medicine, Hokkaido University
Apr 2016-Mar 2020	Director, Institute for Genetic Medicine, Hokkaido University
Apr 2017-Mar 2018	Chairman, The Council of Joint Usage/Research Centers in National Universities
Jun 2021-Present	Group leader, Institute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology
Nov 2021-Present	Professor, Division of Molecular Neuroimmunology, National Institute for Physiological Sciences, National Institutes of Natural Sciences

Details of selected Awards and Honors

A list of selected Publications

Ogura, H, Murakami, Y. Okuyama, M. Tsuruoka1, C. Kitabayashi, M. Kanamoto, M. Nishihara, Y. Iwakura and T. Hirano. Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction. Immunity 29: 628-636, 2008.

Murakami, M., Y. Okuyama, H. Ogura, S. Asano, Y. Arima, M. Tsuruoka, M. Harada, M. Kanamoto, Y. Sawa, Y. Iwakura, K. Takatsu, D. Kamimura and T. Hirano. Local microbleeding facilitates IL-6－ and IL-17－dependent arthritis in the absence of tissue antigen recognition by activated T cells. Exp. Med. 208: 103-114, 2011.

Arima, Y., M. Harada, D. Kamimura, J-H. Park, F. Kawano, F. E. Yull, T. Kawamoto, Y. Iwakura, U.A.K. Betz, G. Ma´rquez, T. S. Blackwell, Y. Ohira, T. Hirano and Murakami. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148: 447-457, 2012

Murakami, M., M. Harada, D. Kamimura, H. Ogura, Y. Okuyama, N. Kumai, A. Okuyama, R. Singh, J.-J. Jiang, T. Atsumi, S. Shiraya, Y. Nakatsuji, M. Kinoshita, H. Kohsaka, M. Nishida, S. Sakoda, N. Miyasaka, K. Yamauchi-Takihara and T. Hirano. Disease-association analysis of an inflammation-related feedback loop. Cell Reports 3: 1-14, 2013.

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 Murakami. KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR. Nat. Commun. 6, Article number: 7474, 2015

Morimoto, P. Wieghofer, Y. Okada, Y. Mori, S. Sakoda, S. Saika, Y. Yoshioka, I. Komuro, T. Yamashita, T. Hirano, M. Prinz, and Murakami. A pain-mediated neural signal induces relapse in multiple sclerosis models. eLife 2: e08733 2015.

Arima, Y., T. Ohki, N. Nishikawa, K. Higuchi, M. Ota, Y. Tanaka, J. Nio-Kobayashi, M. Elfeky, R. Sakai, Y. Mori, T. Kawamoto, A. Stofkova, Y. Sakashita, Y. Morimoto, M. Kuwatani, T. Iwanaga, Y. Yoshioka, N. Sakamoto, A. Yoshimura, M. Takiguchi, S. Sakoda, M. Prinz, D. Kamimura, and Murakami. Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit. eLife 6: e25517, 2017.

Tanaka, H., Y. Arima, D. Kamimura, Y. Tanaka, N. Takahashi, T. Uehata, K. Maeda, T. Satoh, Murakami, and S. Akira. Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response. J Exp Med. Jun 3;216(6):1431-1449, 2019.

Murakami, M., D. Kamimura and T. Hirano. Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines. Immunity. 50, 812-831, 2019.

Stofkova, A., D. Kamimura, T. Ohki, M. Ota, Y. Arima, and Murakami. Photopic light-mediated down-regulation of local α1A-adrenergic signaling protects blood-retina barrier in experimental autoimmune uveoretinitis. Sci Rep. 9, Article number: 2353, 2019.