Suppression of experimental autoimmune encephalomyelitis by anti-midkine RNA aptamers.

2011 Fiscal Year Final Research Report

• Project/Area Number: 22790816
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: SONOBE Yoshifumi 名古屋大学, 大学院・医学系研究科, COE特任助教 (20534845)
• Project Period (FY): 2010 – 2011
• Keywords: 多発性硬化症 / 神経免疫 / 制御性T細胞 / 樹状細胞

Research Abstract

In this study, we investigated how midkine(MK) decreased regulatory CD4^+CD25^+Foxp^<3+> T cells(Tregs) in experimental autoimmune encephalomyelitis(EAE). DCreg expressed produced significantly less IL-12 compared with conventional DCs. However, MK induced IL-12 production by reducing phosphorylated STAT3 levels via src homology region 2 domain. containing phosphatase-2 in DCreg. Inhibiting MK activity with anti-MK RNA aptamers, which binds to the targeted protein to suppress the function of the protein, increased the numbers of CD11c^<low> CD45RB^+DCs and Treg in the draining lymph nodes, and suppressed the severity of EAE, an animal model of multiple sclerosis(MS). Our results also demonstrated that MK was produced by inflammatory cells, and in particular CD4^+T cells under inflammatory conditions. Taken together, these results suggest that MK aggravates EAE by suppressing DCreg development, thereby impairing the Treg population. Thus, MK is a promising therapeutic target for various autoimmune diseases.

Research Products

• [Journal Article] Immunoglobulin G1 immune complex upregulates interferon-γinducednitric oxide production via ERK1/2 activation in murine microglia (2012)
  • Author(s): Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, Mizuno T, Suzumura A
  • Journal Title: J Neuroimmunol Volume: 244(1-2) Pages: 57-62
  • Peer Reviewed
• [Journal Article] Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells (2012)
  • Author(s): Sonobe Y, Li H, Jin S, Kishida S, Kadomatsu K, Takeuchi H, Mizuno T, Suzumura A
  • Journal Title: J Immunol Volume: 188(6) Pages: 2602-2611
  • Peer Reviewed
• [Journal Article] The gap-junction inhibitor Carbenoxolone suppresses the differentiation of Th17 cells through inhibition of IL-23 expression in antigen presenting cells (2011)
  • Author(s): Li E, Jin S, Sonobe Y, Ma D, Li H, Kawanokuchi J, Mizuno T, Suzumura A
  • Journal Title: J Neuroimmunol Volume: 240-241 Pages: 58-64
  • Peer Reviewed
• [Journal Article] Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-βneurotoxicity (2011)
  • Author(s): Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A
  • Journal Title: Am J Pathol Volume: 179 Pages: 2016-2027
  • Peer Reviewed
• [Journal Article] Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease. (2011)
  • Author(s): 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
  • Journal Title: PLoS One Volume: 6 Pages: e21108
  • Peer Reviewed
• [Journal Article] Production and functions of IL-33 in the central nervous system (2011)
  • Author(s): Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A
  • Journal Title: Brain Research Volume: 1385 Pages: 8-17
  • Peer Reviewed
• [Journal Article] IL-9 promotes Th17 cell migration into the central nervous system via CC chemokine ligand-20 produced by astrocytes (2011)
  • Author(s): Zhou Y, Sonobe Y, Akahori T, Jin S, Kawanokuchi J, Noda M, Iwakura Y, Mizuno T, Suzumura A
  • Journal Title: J Immunol Volume: 186 Pages: 4415-4421
  • Peer Reviewed
• [Journal Article] Phenytoin at optimum doses ameliorates experimental autoimmune encephalomyelitis via modulation of immunoregulatory cells (2011)
  • Author(s): Hashiba N, Nagayama S, Araya S, Inada H, Sonobe Y, Suzumura A, Matsui M
  • Journal Title: J Neuroimmunol Volume: 233 Pages: 112-119
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor-a promotes granulocyte-macrophage colony-stimulating factor-stimulated microglia to differentiate into competent dendritic Clin Exp Neuroimmunol cell-like antigen-presenting cell (2011)
  • Author(s): Li H, Sonobe Y, Tabata H, Liang J, Jin S, Doi Y, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A
  • Volume: 2
  • Pages: 1-11
  • Peer Reviewed
• [Journal Article] Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression (2011)
  • Author(s): Noda M, Doi Y, Liang J, Kawanokuchi J, Y, Takeuchi H, Mizuno T, Suzumura A
  • Journal Title: J Biol Chem Volume: 286 Pages: 2308-2319
  • Peer Reviewed
• [Presentation] 脳のinnate immunityの視点から:樹状細胞の役割 (2011)
  • Author(s): 薗部佳史
  • Organizer: 第23回日本神経免疫学会学術集会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2011-09-17
• [Presentation] IL-9はアストロサイトのCCL-20産生を介してTH17の中枢神経への移行を誘導する (2011)
  • Author(s): 薗部佳史、周妍、赤堀友彦、金世杰、川ノ口潤、野田万理子、水野哲也、錫村明生
  • Organizer: 第23回日本神経免疫学会学術集会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2011-09-15
• [Presentation] Midkine exacerbates experimental autoimmune encephalomyelitis through suppressing expansion of regulatory dendritic celL (2010)
  • Author(s): Sonobe Y, Li H, Takeuchi H, Mizuno T, Suzumura A
  • Organizer: 10th International Congress of Neuroimmunology
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2010-10-28
• [Presentation] Midkine exacerbates experimental autoimmune encephalomyelitis through suppressing expansion of regulatory dendritic cell (2010)
  • Author(s): Sonobe Y, Li H, Takeuchi H, Mizuno T, Suzumura A
  • Organizer: Neuroimmunology Kyoto Conference
  • Place of Presentation: ホテル京都ガーデンパレス(京都)
  • Year and Date: 2010-08-19
• [Remarks]
  • URL: http://www.riem.nagoya-u.ac.jp/4/dhnc2.html