Thank you for visiting the website of the Department of Neuroimmune System. Our department was newly established on April 1, 2025. We are dedicated to elucidating the mechanisms underlying the interaction between the nervous and immune systems, with a particular focus on how aging disrupts this complex crosstalk. Through our research, we aim to deepen our understanding of sensory processing and the pathophysiology of age-related diseases, contributing to new insights in the field of neuroimmunology and geroscience.
June 26, 2025 – Gave a lecture titled Introduction to Medical Research to first-year medical students at Nara Medical University.
June 20, 2025 – Our research article was published in the July issue of BIO Clinica.
June 19, 2025 – Presented at the 2nd Geroscience Research Center Seminar.
June 14, 2025 – Participated in the 4th APOE Research Meeting (The ApoE).
June 9, 2025 – Gave a poster presentation at the Keystone Symposia.
June 1, 2025 – Aung Ye Mun joined our team as a research fellow.
May 13, 2025 – We are recruiting a part-time research assistant.
April 11, 2025 – Presented at The 9th NCGG/TMIG – ICAH Symposium.
April 1, 2025 – The Department of Neuroimmunology Systems was established. Tatsuhide Tanaka was appointed as Director, and Yukari Kido joined as a research assistant.
We aim to elucidate the mechanisms underlying various age-related physiological changes and diseases through the lens of neuroimmune interactions. Our research investigates how the breakdown in communication between the nervous and immune systems contributes to sensory decline and the onset of age-associated diseases. By exploring this intricate crosstalk, we seek to uncover novel biological mechanisms of aging and geriatric disorders.
As individuals age, the risk of developing various diseases increases, including a marked rise in the prevalence of chronic pain. Pain frequently accompanies a wide range of diseases, and understanding its underlying mechanisms is essential for developing effective treatments. We believe that identifying the processes involved in pain generation and progression can contribute to improving the quality of life in the elderly. Our research further aims to discover new mechanisms of pain pathogenesis and to develop innovative therapeutic strategies specifically targeting age-related pain.
Chronic pain is a major global health issue, affecting millions of people and causing profound physical, psychological, and social impacts. Current treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, often fall short in providing effective relief. As a result, developing innovative therapeutic approaches to alleviate chronic pain and improve patients' quality of life remains a critical challenge in modern medicine.
Our previous research has demonstrated that macrophages localized near peripheral nerves within the dermal layer of the skin play a key role in pain modulation through the intracellular trafficking-related factor Sorting Nexin 25 (SNX25). We found that SNX25 promotes the expression and secretion of nerve growth factor (NGF), thereby contributing to the induction of pain (Tanaka et al., Nat. Immunol. 2023).
Building on this work, we are now exploring how this sensory regulation system is mediated by nerve-associated macrophages not only in the skin but also in other organs. Our goal is to uncover the underlying molecular mechanisms of pain perception and establish a more comprehensive understanding of pain regulation. Concurrently, we are actively pursuing novel therapeutic strategies targeting SNX25 and its associated factors as potential treatments for chronic pain.
The prevalence of chronic pain increases markedly with age, especially in individuals aged 75 and older. While age-related chronic inflammation is suggested to contribute to chronic pain in the elderly, detailed investigations into the underlying mechanisms remain limited. Our previous studies have demonstrated that alterations in immune cells play a critical role in pain induction. We are now investigating how age-related changes in immune cell function contribute to chronic pain development and persistence.
To elucidate the molecular mechanisms driving chronic pain in the elderly, we employ various pain models using naturally aged mice maintained in our in-house aging colony, “Aging Farm”.
Additionally, we analyze data from the National Institute for Longevity Sciences—Longitudinal Study of Aging (NILS-LSA), a long-term epidemiological study on aging conducted at the National Center for Geriatrics and Gerontology, to examine sensory function and pain in the elderly. This integrative approach allows us to identify age-specific mechanisms and potential therapeutic agents.
Inflammation is a fundamental biological process that defends the host and restores tissue homeostasis by recruiting immune cells to the site of injury. Following peripheral nerve injury, efficient clearance of debris and smooth progression of nerve regeneration are key factors for functional recovery. Among immune cells, macrophages play a central role in the injury response. They contribute to tissue repair and debris clearance through phagocytosis of myelin remnants and secrete either pro- or anti-inflammatory cytokines and growth factors depending on the phase of injury. In addition, macrophages regulate the local immune microenvironment through interactions with other immune cells, such as T and B lymphocytes, and promote axonal regeneration and remyelination in collaboration with Schwann cells.
However, with aging, immune homeostasis becomes dysregulated. Macrophages exhibit reduced phagocytic activity, and immune diversity declines, leading to a persistent, low-grade inflammatory state known as “inflammaging.” These age-associated changes can impair the nerve repair process and contribute to incomplete regeneration.
Our research investigates the cellular and molecular changes in macrophage function using a peripheral nerve regeneration model in aged mice (20–24 months old). These studies aim to lay the foundation for developing innovative regenerative therapies tailored to the needs of the aging population.
Macrophages adhere to the extracellular matrix through specialized structures known as podosomes, which serve as dynamic platforms for sensing external mechanical forces and detecting information such as deformation of the surrounding tissue. We are investigating whether this mechanosensing via podosomes in macrophages is impaired in age-related diseases, aiming to uncover how the interplay between mechanical stress and aging contributes to disease progression. For instance, in conditions such as atherosclerosis and cancer—both of which become more prevalent with age—the affected tissues often become abnormally stiff. Our research seeks to elucidate how macrophages respond to these mechanical alterations through mechanotransduction pathways, ultimately providing novel insights into the pathophysiology of aging and geriatric disorders from a mechanobiological perspective.
Tanaka T*, Isonishi A, Banja M, Yamamoto R, Sonobe M, Okuda-Ashitaka E, Furue H, Okuda H, Tatsumi K and Wanaka A. Sci. Rep. 14 27192 2024
Mun AY, Akiyama K*, Wang Z, Zhang J, Kitagawa W, Kohno T, Tagashira R, Ishibashi K, Matsunaga N, Zou T, Ono M, Kukobi T. Journal of Bone and Mineral Research Plus. 8 (8): ziae085. 2024
Tanaka T*, Okuda H, Isonishi A, Terada Y, Kitabatake M, Shinjo T, Nishimura K, Takemura S, Furue H, Ito T, Tatsumi K, Wanaka A*. Nat. Immunol. 24: 439-451. 2023
Tanaka T*, Ohno N, Osanai Y, Saitoh S, Thai TQ, Nishimura K, Shinjo T, Takemura S, Tatsumi K, Wanaka A. GLIA 69: 2488-2502. 2021
Tanaka T*, Murakami K, Bando Y, Nomura T, Isonishi A, Morita-Takemura S, Tatsumi K, Wanaka A, Yoshida S. Neurochem. Int. 108: 332-342, 2017
Tanaka T*, Murakami K, Bando Y, Yoshida S. GLIA. 63: 595-610, 2015
Tanaka T*, Murakami K, Bando Y, Yoshida S. J. Neurochem. 127: 259-270, 2013
Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, Yamashita T. Nat. Neurosci. 16: 543-551, 2013
Tanaka T, Ueno M, Yamashita T. J. Biol. Chem. 284: 21626-21636, 2009
| Professor | Tatsuhide Tanaka |
| Researcher | Aung Ye Mun |
| Research Assistant | Yukari Kido |
Achievements since 2020
Ueda K, Imai T, Okayasu T, Tanaka T, Tatsumi K, Wanaka A, Kitahara T. Coenzyme Q10 and rikkunshito prevent age-related changes in mouse otolith morphology and function. Biochemistry and Biophysics Reports in press 2025
Isonishi A, Tatsumi K, Okuda H, Tanaka T, Hattori T, Wanaka A. Macrophage deficiency of sorting nexin 25 suppress plaque formation in atherosclerotic lesions in mice. Acta Histochemica et Cytochemica 58: 1-6. 2025
Tanaka T*, Isonishi A, Banja M, Yamamoto R, Sonobe M, Okuda-Ashitaka E, Furue H, Okuda H, Tatsumi K, Wanaka A. Dermal macrophages control tactile perception under physiological conditions via NGF signaling. Sci. Rep. 14 27192 2024
Ueda K, Imai T, Ito T, Okayasu T, Harada S, Kamakura T, Ono K, Katsuno T, Tanaka T, Tatsumi K, Hibino H, Wanaka A, Kitahara T. Effects of aging on otolith morphology and functions in mice. Front Neurosci. 18: 1466514. 2024
Mun AY, Akiyama K*, Wang Z, Zhang J, Kitagawa W, Kohno T, Tagashira R, Ishibashi K, Matsunaga N, Zou T, Ono M, Kukobi T. Macrophages modulate mesenchymal stem cell function via tumor necrosis factor alpha in tooth extraction model. Journal of Bone and Mineral Research Plus. 8 (8): ziae085. 2024
Kawaguchi AT, Tanaka T, Yamano M, Sumiyoshi H, Kitagishi H, Yamada Y, Kawaguchi G, Bergsland J. Carboxyhemoglobin Particle Infusion, but not Carbon Monoxide Inhalation ameliorates Myocardial Infarction via Attenuated Oxidative Stress and In Situ Inflammation in a Rat Model. Medical Research Archives. 11: 11. 2023
Mitani S, Tanaka T, Isonishi A, Tatsumi K, Momota Y, Wanaka A, Sorting nexin 25 regulates C5ainduced nerve growth factor expression in macrophagelike J774.1 cells. J. Osaka Dent. Univ. 57: 55-62. 2023
Tanaka T*, Okuda H, Isonishi A, Terada Y, Kitabatake M, Shinjo T, Nishimura K, Takemura S, Furue H, Ito T, Tatsumi K, Wanaka A*, Dermal macrophages set pain sensitivity by modulating the amount of tissue NGF through an SNX25–Nrf2 pathway. Nat. Immunol. 24: 439-451. 2023
Nakahara K, Okuda H, Isonishi A, Kawabe Y, Tanaka T, Tatsumi K, Wanaka A, Amino acid transporter Asc-1 (SLC7A10) expression is altered in basal ganglia in experimental Parkinsonism and L-dopa-induced dyskinesia model mice. Journal of Chemical Neuroanatomy. 127: 102191. 2023
Takemura S, Isonishi A, Horii-Hayashi N, Tanaka T, Tatsumi K, Komori T, Yamamuro K, Yamano M, Nishi M, Makinodan M, Wanaka A., Juvenile social isolation affects the structure of the tanycyte–vascular interface in the hypophyseal portal system of the adult mice. Neurochemistry International. 162: 105439. 2023
Kawabe Y, Tanaka T, Isonishi A, Nakahara K, Tatsumi K, Wanaka A, Characterization of Glial Populations in the Aging and Remyelinating Mouse Corpus Callosum. Neurochemical Research. 47: 2826-2838. 2022
Tatsumi K, Kinugawa K, Isonishi A, Kitabatake M, Okuda H, Takemura S, Tanaka T, Mori E, Wanaka A, Olig2-astrocytes express neutral amino acid transporter SLC7A10 (Asc-1) in the adult brain. Molecular Brain. 14: 163. 2021
Tanaka T*, Ohno N, Osanai Y, Saitoh S, Thai TQ, Nishimura K, Shinjo T, Takemura S, Tatsumi K, Wanaka A. Large-scale electron microscopic volume imaging of interfascicular oligodendrocytes in the mouse corpus callosum. GLIA 69: 2488-2502. 2021
Iwasa N, Matsui TK, Iguchi N, Kinugawa K, Morikawa N, Sakaguchi YM, Shiota T, Kobashigawa S, Nakanishi M, Matsubayashi M, Nagata R, Kikuchi S, Tanaka T, Eura N, Kiriyama T, Izumi T, Saito K, Kataoka H, Saito Y, Kimura W, Wanaka A, Nishimura Y, Mori E, Sugie K. Gene expression profiles of human cerebral organoids identify PPAR pathway and PKM2 as key markers for oxygen-glucose deprivation and reoxygenation. Front Cell Neurosci. 15: 605030 2021
Nishimura K, Tanaka T*, Takemura S, Tatsumi K, Wanaka A. SNX25 regulates proinflammatory cytokine expression via the NF-kB signal in macrophages. PLOS ONE. 16 (3): e0247840. 2021
Takemura S, Isonishi A, Tanaka T, Okuda H, Tatsumi K, Yamano M, Wanaka A. Neural expression of sorting nexin 25 and its regulation of tyrosine receptor kinase B trafficking. Brain Struc Funct. 225: 2615-2642. 2020
Takemura S, Nagano M, Isonishi A, Tanaka T, Tatsumi K, Yamano M, Minami Y, Shigeyoshi Y, Wanaka A. Circadian rhythms of sorting nexin 25 in the mouse suprachiasmatic nucleus. Neurosci Lett. 727: 134897, 2020
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Department of Neuroimmune System
Geroscience Research Center
Research Institute, National Center for Geriatrics and Gerontology
7-430 Morioka-cho, Obu city, Aichi 474-8511, Japan
ttanaka[at]ncgg.go.jp
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