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Akio Suzumura MD, PhDProfessor, Department of Neuroimmunology, Nagoya University Graduate School of Medicine (Research Institute of Environmental Medicine)


Specialized field

Neuroimmunology, Pathophysiology of glial cells

Career Summary

1975
Graduated from Gifu University, School of Medicine
1983
MD degree (Nagoya University)
1983-1986
Post-doctoral fellow at Dept. Neurol, University of Pennsylvania
1987
Dept. Neurol., Fujita Health Univerisity, Assist. Professor
1995
Dept. Neurol., Nara Medical University, Assoc. Professor
2001
Dept. Neuroimmunol., RIEM, Nagoya University, Professor

Research Theme

Immunological therapy against neurological diseases

Research Summary

Neuron-glia interaction via signal molecules from damaged neurons

Microglia, macrophage-like resident immune cells in the central nervous system, accumulate in the lesions observed in such neurodegenerative disorders as Alzheimer’s disease (AD), where this cell type is thought to have both neurotoxic and neuroprotective properties. When activated, microglia release a variety of inflammatory and neurotoxic molecules including inflammatory cytokines, nitric oxide, reactive oxygen species and glutamate, resulting in neuronal damage. On the other hand, microglia also release neuroprotective factors and anti-inflammatory cytokines, and remove unwanted debris via phagocytosis. We have shown previously that activation of microglia occur via soluble factors from damaged neurons. One of the factors is CX3C chemokine, fractalkine (sFKN) which is secreted from neurons that have been damaged by glutamate, promotes microglial phagocytosis of neuronal debris through release of milk fat globule-EGF factor 8 (MFG-E8), a mediator of apoptotic cell clearance. In addition, sFKN induces the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in microglia in the absence of neurotoxic molecule production, including NO, TNFα, and glutamate. In this study, we show that another factor from damaged neurons is interleukin-34 (IL-34). When exposed to oligomer amyloid β (oAβ), neurons produced and secreted IL-34 as determined by RT-PCR for mRNA expression and by ELISA for secreted protein. Thus produced IL-34 dose-dependently suppressed oAβ-induced neuronal cell death. Since the receptor for IL-34 was expressed in microglia, we examined the effects of IL-34 on microglia. IL-34 dose-dependently induced proliferation of microglia, production of HO-1 and insulin degrading enzyme (IDE).
In conclusion, IL-34 is a help-me signal from damaged neurons and exerts neuroprotective functions by upregulating anti-oxidant and Aβ clearance activities by microglia.

Principal Research Achievement

  1. Sonobe Y, Li H, Jin S, Kishida S, Kadomatsu K, Takeuchi H, Mizuno T, Suzumura A: Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells. J Immunol, 188, 2602-2611 (2012)
  2. Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, Mizuno T, Suzumura A: Immunoglobulin G(1) immune complex upregulates interferon-gamma-induced nitric oxide production via ERK1/2 activation in murine microglia. J Neuroimmunol, 244, 57-62 (2012)
  3. Zhou Y, Sonobe Y, Akahori T, Jin S, Kawanokuchi J, Noda M, Iwakura Y, Mizuno T, Suzumura A: IL-9 promotes Th17 cell migration into the central nervous system via CC chemokine ligand-20 produced by astrocytes. J Immunol, 186, 4415-4421 (2011)
  4. Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A: Production and functions of IL-33 in the central nervous system. Brain Res, 1385, 8-17 (2011)
  5. Takeuchi H, Mizoguchi H, Doi Y, Jin S, Noda M, Liang J, Li H, Zhou Y, Mori R, Yasuoka S, Li E, Parajuli B, Kawanokuchi J, Sonobe Y, Sato J, Yamanaka K, Sobue G, Mizuno T, Suzumura A: Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease. PLoS One, 6, e21108 (2011)
  6. Noda M, Doi Y, Liang J, Kawanokuchi J, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A: Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem, 286, 2308-2319 (2011)
  7. Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A: Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am J Pathol, 179, 2016-2027 (2011)
  8. Hashiba N, Nagayama S, Araya SI, Inada H, Sonobe Y, Suzumura A, Matsui M: Phenytoin at optimum doses ameliorates experimental autoimmune encephalomyelitis via modulation of immunoregulatory cells. J Neuroimmunol, 233, 112-119 (2011)
  9. Endong L, Shijie J, Sonobe Y, Di M, Hua L, Kawanokuchi J, Mizuno T, Suzumura A: The gap-junction inhibitor carbenoxolone suppresses the differentiation of Th17 cells through inhibition of IL-23 expression in antigen presenting cells. J Neuroimmunol, 240-241, 58-64 (2011)
  10. Liang J, Takeuchi H, Jin S, Noda M, Li H, Doi Y, Kawanokuchi J, Sonobe Y, Mizuno T, Suzumura A. Glutamate induces neurotrophic factors release from microglia via PKC pathway. Brain Res, 1322, 8-23 (2010)
  11. Sonobe Y, Takeuchi H, Kataoka K, Li H, Jin S. Mimuro M, Hashizume Y, Sano Y, Kanda T, Mizuno T, Suzumura A. Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Ce-dependent manner. J Biol Chem, 284, 31834-31842 (2009)
  12. Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M i, Doi M, Michikawa M, Takeuchi H, Suzumura A. Microglia activated with toll-like receptor 9 ligand CpG attenuate oligomeric amyloid-b neurotoxicity in vitro and in vivo models of Alzheimer's disease. Am J Pathol, 175, 2121-2131 (2009)
  13. Shijie J, Takeuchi H, Yawata I, Harada Y, Sonobe Y, Doi Y, Liang J, Hua L, Yasuoka S, Zhou Y, Noda M, Kawanokuchi J, Mizuno T, Suzumura A. Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice. Tohoku J Exp Med, 17, 87-92 (2009)
  14. Takeuchi H, Jin S, Suzuki H, Doi Y, Liang J, Kawanokuchi J, Mizuno T, Sawada M, Suzumura A. Blockade of microglial glutamate release protects against ischemic brain injury. Exp Neurol, 214, 144?146 (2008)
  15. Wang J, Takeuchi H, Sonobe Y, Jin S, Mizuno T, Miyakawa S, Fujiwara M, Nakamura Y, Kato T, Muramatsu H, Muramatsu T, Suzumura A. Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population. Proc Natl Acad Sci USA, 105, 3915-3920 (2008)
  16. Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, Jin S, Takada N, Komatsu Y, Suzumura A. Interferon-g directly induces neurotoxicity through a neuron specific, calcium- permeable complex of IFN-g receptor and AMPA GluR1 receptor. FASEB J, 22, 1797-1806 (2008)
  17. Yawata I, Takeuchi H, Doi Y, Liang J, Mizuno T, Suzumura A. Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors.Life Sci, 82, 1111-1116 (2008)
  18. Liang J, Takeuchi H, Kawanokuchi J, Sonobe Y, Yawata I, Yasuoka S, Mizuno T, Suzumura A. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res, 1210, 11-19 (2008)
  19. Sonobe Y, Liang J, Jin S, Zhang G, Takeuchi H, Mizuno T, Suzumura A. Microglia express a functional receptor for interleukin-23. Biochem Biophys Res Commun, 370, 129-133 (2008)
  20. Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A. Production and functions of IL-17 in microglia. J Neuroimmunol,194, 54-61 (2008)
  21. Takeuchi H et al. Tumor necrosis factor-a induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J. Biol. Chem. 281:21362-21368 (2006)
  22. Takeuchi H et al. Iterferon-g induces microglial activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis. Neurobiol Dis. 22: 33-39 (2006)
  23. Takeuchi H et al. Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J. Biol. Chem. 280: 10444-10454 (2005)
  24. Kawanokuchi J et al. Effects of interferon-g n microglial functions as inflammatory and antigen presenting cells in the central nervous system. Neuropharmacol. 46: 734-742 (2004)
  25. Mizuno T et al. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacol., 46: 404-411 (2004)
  26. Inoue H et al. Serial analysis of gene expression in a microglial cell line. Glia 28: 265-271 (1999)
  27. Sawada M et al. IL-10 inhibits both production of cytokine and expression of cytokine receptors in microglia. J. Neurochem. 72: 1466-1471 (1999)
  28. Matsumura R et al. Spinocerebellar ataxia type 6: Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology 49: 1238-1243 (1997)
  29. Suzumura A et al. Transforming growth factor-b suppresses activation and proliferation of microglia in vitro. J. Immunol. 151: 2150-2158 (1993)
  30. Sawada M et al. Human T-cell leukemia virus type I trans activator induces class I major histocompatibility complex antigen expression in glial cells. J. Virology 64: 4002-4006 (1990)
  31. Suzumura A et al. Induction of glial cell MHC antigen expression in neurotropic corona virus infection; characterization of the H-2 inducing soluble factor elavorated by infected brain cells. J. Immunol. 140: 2068-2072 (1988)
  32. Suzumura A et al. Coronavirus infection induces H-2 antigen expression on oligodendrocytes and astrocytes. Science 232: 991-993 (1986)

Award

1992 Research Award for intractable neurological disease, “Basic and clinical studies on multiple sclerosis” from Aichi Medical Association.
1996 Research Award from the Naito Foundation, “The mechanisms and treatment for neurological disorders caused by immune-mediated and virus-induced mechanisms.”

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