Embargoed until May 17, 2022 10.00 EDT (23.00 JST)ATP from sensory neuron-interneuron crosstalk is key to spreading
inflammation in Rheumatoid Arthritis
Joint release by Hokkaido University, National Institute for Physiological Sciences (NIPS),
National Institutes for Quantum Science and Technology (QST), and Japan Agency for
Medical Research and Development (AMED).
Adenosine triphosphate (ATP) secreted from sensory neuron-interneuron
crosstalk is key to the spreading of inflammation across joints, acting as aneurotransmitter and inflammation enhancer.

Rheumatoid Arthritis (CC BY-NC 2.0 Leides Moura).

Rheumatoid arthritis is a chronic inflammatory autoimmune disorder that primarily
affects joints. One of the key features of this disease is remote inflammation, whereinflammation spreads from one joint to another. Research has shown that neuralcircuits or cells migrated from the joints are involved in inflammation spread, but thedetailed mechanism by which this occurs has not been elucidated.

A team of researchers from Japan and the USA, led by Professor Masaaki Murakami at
Hokkaido University, have revealed that remote inflammation spreads by neuron
crosstalk, and that adenosine triphosphate (ATP) plays a key role in this process. Theirfindings, published in the Journal of Experimental Medicine, may lead to new therapies
and treatments for inflammatory diseases.

Inflammation is a part of the natural immune response that occurs in response toinfection or irritation. It is a process by which the immune system, involving immune
cells, blood vessels, and molecular mediators, attempts to clear out the pathogens anddamaged cells and thereafter repair the damage. However, excessive inflammation is adisorder in itself, and is seen in diseases such as hay fever, atherosclerosis, psoriasis,and rheumatoid arthritis, among others.

In this study, the authors used previous observations of the gateway reflex—an immune
response mechanism whereby specific neural signals change the state of specific bloodvessels to allow immune cells to enter tissue, leading to local inflammation—tohypothesize that neural crosstalk could be responsible for remote inflammation.

They tested this hypothesis through experiments in rheumatoid arthritis models inmice. The mice were divided into control and test groups. In the test groups, the sensory
neural circuits between the left and right ankle joints were interrupted. Arthritis of theleft ankle was then induced in both sets of mice and the spread of arthritis to the rightankle was observed.
Their results showed that the inflammation signal in one joint is transmitted to theother via a sensory neuron connection through the spinal cord, leading to inflammationin both joints. Specifically, inflammation in one joint led to an increase of ATP in bothjoints, which triggered an increase of a signal molecule that resulted in inflammation.
Blocking this pathway prevented the spread of inflammation.

The inflammation signal (IL-6 amplifier) in the affected joint (L) causes the secretion of ATP thattransmits a signal through the spinal cord (DRG, L5), which in turn triggers an increase in ATP
concentrations in the unaffected joint (R) that results in inflammation in that joint (Rie Hasebe,
et al. Journal of Experimental Medicine. May 10, 2022).

As this study was performed in mice models, it is necessary to determine if the findings
apply to rheumatoid arthritis and other chronic inflammatory diseases in humans. If so,
it could provide a therapeutic target for various diseases with spreading inflammation.
###The researchers involved in this study include Rie Hasebe, Kaoru Murakami, NadaHalaka, Junko Nio-Kobayashi, Toshihiko Iwanaga, Masahiko Watanabe, Daisuke
Kamimura, Yuki Tanaka, Masaaki Murakami at Hokkaido University. Rie Hasebe is alsoaffiliated with the National Institute for Physiological Sciences (NIPS) and the Moonshot
Research and Development Project, Japan Agency for Medical Research andDevelopment (AMED); Yuki Tanaka is also affiliated with the National Institutes for
Quantum Science and Technology (QST) and the Moonshot Research and Development
Project, Japan Agency for Medical Research and Development (AMED); and Masaaki
Murakami is also affiliated with affiliated with the National Institute for PhysiologicalSciences (NIPS), the National Institutes for Quantum Science and Technology (QST), andthe Moonshot Research and Development Project, Japan Agency for Medical Researchand Development (AMED).

The Murakami group at Hokkaido University. Rie Hasebe (third row, right; white long-sleeved
shirt holding a blue jacket), Kaoru Murakami (last row, left; dark violet scrubs), Yuki Tanaka(second row, center; gray zip-up hoodie), and Masaaki Murakami (first row, center; black zip-uphoodie) are key contributors to the paper. (Photo: Masaaki Murakami)

Original Article:
Rie Hasebe, et al. ATP spreads inflammation to other limbs through crosstalk between
sensory neurons and interneurons. Journal of Experimental Medicine. May 10, 2022.
DOI: 10.1084/jem.20212019

Funding:
This work was supported by Japan Society for the Promotion of Science(JSPS) KAKENHI; Ministry of Education, Culture, Sports, Science and Technology(MEXT) Quantum Leap Flagship Program (Q-LEAP; JPMXS0120330644); Japan Agencyfor Medical Research and Development (AMED); Takeda Science Foundation; Institutefor Fermentation Osaka; Mitsubishi Foundation; Chugai Pharma Research Grant; andAkiyama Life Science Foundation. This study was also supported partly by the Grant forJoint Research Program of the Institute for Genetic Medicine, Hokkaido University, by
the Photo-excitonix Project, Hokkaido University, and by the Promotion Project for
Young Investigators at Hokkaido University.
Contacts:
Researchers
Professor Masaaki Murakami
Division of Molecular Psychoneuroimmunology
Institute for Genetic Medicine

Graduate School of Medicine
Hokkaido University
Tel: +81-11-706-5120
Email: murakami[at]igm.hokudai.ac.jp

Innovative and Advanced Research and Development Section
Seeds Development and Research Platform Division
Japan Agency for Medical Research and Development
Tel: +81-3-6870-2224
E-mail: kenkyuk-ask@amed.go.jp

Institutions
Sohail Keegan Pinto (International Public Relations Specialist)
Public Relations Division
Hokkaido University
Tel: +81-11-706-2185
Email: en-press[at]general.hokudai.ac.jp
Research Enhancement Strategy Office
National Institute for Physiological Sciences (NIPS)
Tel: +81-564-55-7723
Email: pub-adm[at]nips.ac.jp

Public Relations Division, Corporate Planning Department
National Institute for Quantum Science and Technology
Tel: +81-43-206-3026
Email: info[at]qst.go.jp

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