A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model
Open accessAbstract
Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.
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Pain sensation induces a relapse of EAE by activating the IL-6 Amp through another sensory-sympathetic neural network.
“Further, pain sensation induces a relapse of EAE by activating the IL-6 Amp through another sensory–sympathetic neural network (55).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [55]
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Hirobumi, I. (2024) · Cureus · doi:10.7759/cureus.63182 · Cited by 6 · see citing works
Computer model of IL-6-dependent rheumatoid arthritis in F759 mice
Yamamoto, R., Yamada, S., Atsumi, T., Murakami, K., Hashimoto, A., Naito, S., Tanaka, Y., Ohki, I., Shinohara, Y., Iwasaki, N., et al. (2023) · International Immunology · doi:10.1093/intimm/dxad016 · Cited by 6 · see citing works
Self-citationThe gateway reflex regulates tissue-specific autoimmune diseases
Tanaka, Y., Ohki, I., Murakami, K., Ozawa, S., Wang, Y., & Murakami, M. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00325-6 · Cited by 6 · see citing works
Self-citationEffects of cigarette smoke exposure on a mouse model of multiple sclerosis
Ho, J., Koshibu, K., Xia, W., Luettich, K., Kondylis, A., Garcia, L., Phillips, B. W., Peitsch, M. C., & Hoeng, J. (2022) · Toxicology Reports · doi:10.1016/j.toxrep.2022.03.032 · Cited by 5 · see citing works
Gateway reflex: Local neuroimmune interactions that regulate blood vessels
Kamimura, D., Ohki, T., Arima, Y., Ota, M., & Murakami, M. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.09.011 · Cited by 5 · see citing works
Self-citationRNF213–TRAF2 interaction enhances inflammatory responses via NF-κB activation in moyamoya disease
Yasuda, M., Murakami, K., Jiang, J.-J., Ito, M., Tanaka, Y., Tanaka, H., Hasebe, R., Yamasaki, T., Hashimoto, A., Kubota, S. I., et al. (2026) · International Immunology · doi:10.1093/intimm/dxag011 · Cited by 4 · see citing works
Self-citationHoelz, A. G., Bernardes, D., Cartarozzi, L. P., & de Oliveira, A. L. R. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.921916 · Cited by 4 · see citing works
Matsuyama, S., Yamamoto, R., Murakami, K., Takahashi, N., Nishi, R., Ishii, A., Nio‐Kobayashi, J., Abe, N., Tanaka, K., Jiang, J., et al. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200567 · Cited by 4 · see citing works
Self-citationZloh, M., Kutílek, P., Hejda, J., Fišerová, I., Kubovčiak, J., Murakami, M., & Štofková, A. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122996 · Cited by 3 · see citing works
Self-citationShiba, N., Inaba, Y., Motobayashi, M., Nishioka, M., Kawasaki, Y., Noda, S., Matsuura, H., Kobayashi, N., Matsuoka, T., Nakamura, A., et al. (2018) · Case Reports in Pediatrics · doi:10.1155/2018/6931206 · Cited by 3 · see citing works
Pain is an inducer for relapse in multiple sclerosis models through a regional neural signal
Arima, Y., Higuchi, K., Nishikawa, N., Štofková, A., Ohki, T., Kamimura, D., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12250 · Cited by 2 · see citing works
Self-citationTeoh, Y. B., Jiang, J., Yamasaki, T., Nagata, N., Sugawara, T., Hasebe, R., Ohta, H., Sasaki, N., Yokoyama, N., Nakamura, K., et al. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2023.1192888 · Cited by 2 · see citing works
Self-citationElfeky, M., Kamimura, D., Arima, Y., Murakami, M., & Steinman, L. (2017) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12399 · Cited by 2 · see citing works
Self-citationInflammation amplifier and gateway reflex: The regulation of inflammation by neuroimmune interaction
Nakagawa, I., & Murakami, M. (2017) · Japanese Journal of Clinical Immunology · doi:10.2177/jsci.40.160 · Cited by 2 · see citing works
Self-citationAkabane, K., Murakami, K., & Murakami, M. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2225215 · Cited by 1 · see citing works
Self-citationNeural signaling in immunology: the gateway reflex
Hasebe, R., Tanaka, H., Yamasaki, T., Murakami, K., & Murakami, M. (2025) · International Immunology · doi:10.1093/intimm/dxaf009 · Cited by 1 · see citing works
Self-citationKamimura, D., Arima, Y., Atsumi, T., Meng, J., Sabharwal, L., Bando, H., Ogura, H., Jiang, J., Huseby, E. S., & Murakami, M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800763-1.00006-3 · Cited by 1 · see citing works
Self-citationKamimura, D., Arima, Y., Štofková, A., Nishikawa, N., Higuchi, K., Ohki, T., & Murakami, M. (2016) · InTech eBooks · doi:10.5772/62938 · Cited by 1 · see citing works
Self-citationGateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development
Kamimura, D., Tanaka, Y., Ohki, T., & Murakami, M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.77112 · Cited by 1 · see citing works
Self-citationThe gateway reflex: breaking through the blood barriers
Murakami, K., Tanaka, Y., & Murakami, M. (2021) · International Immunology · doi:10.1093/intimm/dxab064 · Cited by 1 · see citing works
Self-citationHiguchi, K., Kamimura, D., Štofková, A., Nishikawa, N., Ohki, T., Arima, Y., & Murakami, M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805298-3.00005-0
Self-citationRecent advances in neuroimmune interactions
Murakami, M. (2017) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12382
Self-citationStress‐gateway reflex: Chronic stress induces fatal organ dysfunctions through a new neural circuit
Murakami, M. (2017) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12418
Self-citationIn situ Microinflammation Detection Using Gold Nanoclusters and a Tissue-clearing Method
Naim, F., Hasebe, R., Hojyo, S., Shichibu, Y., Ishii, A., Tanaka, Y., Tainaka, K., Kubota, S. I., Konishi, K., & Murakami, M. (2023) · BIO-PROTOCOL · doi:10.21769/bioprotoc.4644
Self-citationResearch Progress on the Mechanisms of Pain in Rheumatoid Arthritis
周, 士. (2023) · Advances in Clinical Medicine · doi:10.12677/acm.2023.13102157
Tanaka, Y., Wang, Y., Tanaka, H., Hojyo, S., Kamiya, N., Murakami, K., & Murakami, M. (2026) · Discover Nano · doi:10.1186/s11671-026-04830-0
Self-citationAl-Mazroua, H., Alhamami, H. N., Nadeem, A., Ansari, M. A., Bakheet, S., Attia, S., Sarawi, W., Alomar, H., Alsaad, A., Alshamrani, A. A., et al. (2026) · Immunopharmacology and immunotoxicology · doi:10.1080/08923973.2026.2723386
- Authors
- Arima, Y., Kamimura, D., Atsumi, T., Harada, M., Kawamoto, T., Nishikawa, N., Stofkova, A., Ohki, T., Higuchi, K., Morimoto, Y., Wieghofer, P., Okada, Y., Mori, Y., Sakoda, S., Saika, S., Yoshioka, Y., Komuro, I., Yamashita, T., Hirano, T., Prinz, M., & Murakami, M.
- Affiliations
- Hokkaido University (JP)
- Tsurumi University (JP)
- Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- University of Freiburg (DE)
- Wakayama Medical University (JP)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Toneyama National Hospital (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
- Corresponding author
- Murakami, Masaaki
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-08-11
- Volume
- 4
- Pages
- e08733
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4530187
- OpenAlex
- W1836377684
- Cited by
- 66
- References
- 55
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 11 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 5 · 2017: 12 · 2016: 3 · 2015: 2 · 2014: 1
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion, cc-by)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Takeda Science Foundation
- Naito Foundation
- KAKENHI
- Institute for Fermentation, Osaka
- Mitsubishi Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
- Japan Prize Foundation
- Ono Medical Research Foundation
- Kanzawa Medical Research Foundation
- Kishimoto Foundation
- Nagao Takeshi Research Foundation
- Tokyo Medical Research Foundation
- Japan Society for the Promotion of Science (Postdoctoral Fellowship for Foreign Researchers)
- JST-CREST program
- Osaka Foundation for the Promotion of Clinical Immunology
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- experimental autoimmune encephalomyelitis, multiple sclerosis, pain, recurrence, chemokines, antigen presentation, CD4+ T cells, spinal cord, endothelial cells
- MeSH terms
- Animals, Antigen-Presenting Cells, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Pain, Recurrence, Spinal Cord, CD4-Positive T-Lymphocytes, Chemokines, Mice
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