Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron–interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side. Mechanistic analysis showed that ATP serves as both a neurotransmitter and an inflammation enhancer, thus acting as an intermediary between the local inflammation and neural pathway that induces inflammation on the other side. These results suggest blockade of this neural pathway, which is named the remote inflammation gateway reflex, may have therapeutic value for inflammatory diseases, particularly those, such as rheumatoid arthritis, in which inflammation spreads to remote positions.
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6 June 2022
Brief Definitive Report|
May 17 2022
ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons
In Special Collection:
Neuroimmunology and Neurodegeneration
Rie Hasebe
,
(Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft)
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
2
Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan
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Kaoru Murakami
,
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Masaya Harada
,
4
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
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Nada Halaka
,
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Hiroshi Nakagawa
,
Hiroshi Nakagawa
(Methodology, Writing - original draft)
5
Department of Molecular Neurosciences, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
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Fuminori Kawano
,
Fuminori Kawano
(Investigation, Methodology)
6
Department of Health and Sports Sciences, Graduate School of Medicine, and Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
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Yoshinobu Ohira
,
Yoshinobu Ohira
(Conceptualization)
6
Department of Health and Sports Sciences, Graduate School of Medicine, and Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
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Tadafumi Kawamoto
,
Tadafumi Kawamoto
(Investigation, Methodology, Resources)
7
Radioisotope Research Institute, Department of Dental Medicine, Tsurumi University, Yokohama, Japan
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Fiona E. Yull
,
Fiona E. Yull
(Resources)
8
Department of Pharmacology, Vanderbilt University, Nashville, TN
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Timothy S. Blackwell
,
Timothy S. Blackwell
(Methodology)
9
Department of Medicine, Vanderbilt University, Nashville, TN
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Junko Nio-Kobayashi
,
Junko Nio-Kobayashi
(Investigation)
10
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Toshihiko Iwanaga
,
Toshihiko Iwanaga
(Investigation)
10
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Masahiko Watanabe
,
Masahiko Watanabe
(Resources)
11
Department of Anatomy, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Nobuhiro Watanabe
,
Nobuhiro Watanabe
(Investigation, Visualization)
12
Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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Harumi Hotta
,
Harumi Hotta
(Conceptualization, Investigation, Methodology, Writing - original draft)
12
Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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Toshihide Yamashita
,
Toshihide Yamashita
(Methodology)
5
Department of Molecular Neurosciences, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
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Daisuke Kamimura
,
Daisuke Kamimura
(Investigation)
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Yuki Tanaka
,
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
3
Group of Quantumimmunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan
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Masaaki Murakami
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
2
Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan
3
Group of Quantumimmunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan
Correspondence to Masaaki Murakami: murakami@igm.hokudai.ac.jp
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Rie Hasebe
Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
2
Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
4
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Hiroshi Nakagawa
Methodology, Writing - original draft
5
Department of Molecular Neurosciences, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
Fuminori Kawano
Investigation, Methodology
6
Department of Health and Sports Sciences, Graduate School of Medicine, and Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
Yoshinobu Ohira
Conceptualization
6
Department of Health and Sports Sciences, Graduate School of Medicine, and Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
Tadafumi Kawamoto
Investigation, Methodology, Resources
7
Radioisotope Research Institute, Department of Dental Medicine, Tsurumi University, Yokohama, Japan
Fiona E. Yull
Resources
8
Department of Pharmacology, Vanderbilt University, Nashville, TN
Timothy S. Blackwell
Methodology
9
Department of Medicine, Vanderbilt University, Nashville, TN
Junko Nio-Kobayashi
Investigation
10
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Toshihiko Iwanaga
Investigation
10
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Masahiko Watanabe
Resources
11
Department of Anatomy, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Nobuhiro Watanabe
Investigation, Visualization
12
Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Harumi Hotta
Conceptualization, Investigation, Methodology, Writing - original draft
12
Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Toshihide Yamashita
Methodology
5
Department of Molecular Neurosciences, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
Daisuke Kamimura
Investigation
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
3
Group of Quantumimmunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan
Masaaki Murakami
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
2
Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan
3
Group of Quantumimmunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan
Correspondence to Masaaki Murakami: murakami@igm.hokudai.ac.jp
*
R. Hasebe, K. Murakami, M. Harada, N. Halaka, and Y. Tanaka contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
September 28 2021
Revision Received:
January 26 2022
Accepted:
March 16 2022
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding
Funder(s):
Japan Society for the Promotion of Science
- Award Id(s): JPMXS0120330644
Funder(s):
Japan Agency for Medical Research and Development
Funder(s):
Takeda Science Foundation
Funder(s):
Institute for Fermentation, Osaka
Funder(s):
Mitsubishi Foundation
Funder(s):
Chugai Pharma Research
Funder(s):
Akiyama Life Science Foundation
Funder(s):
Hokkaido University
© 2022 Hasebe et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2022) 219 (6): e20212019.
Article history
Received:
September 28 2021
Revision Received:
January 26 2022
Accepted:
March 16 2022
Citation
Rie Hasebe, Kaoru Murakami, Masaya Harada, Nada Halaka, Hiroshi Nakagawa, Fuminori Kawano, Yoshinobu Ohira, Tadafumi Kawamoto, Fiona E. Yull, Timothy S. Blackwell, Junko Nio-Kobayashi, Toshihiko Iwanaga, Masahiko Watanabe, Nobuhiro Watanabe, Harumi Hotta, Toshihide Yamashita, Daisuke Kamimura, Yuki Tanaka, Masaaki Murakami; ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons. J Exp Med 6 June 2022; 219 (6): e20212019. doi: https://doi.org/10.1084/jem.20212019
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