腸管粘膜固有層のTLR5発現樹状細胞による細菌感染防御機構

• Project Area: Matrix of Infection Phenomena
• Project/Area Number: 21022028
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 植松 智 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (50379088)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2010: ¥2,000,000 (Direct Cost: ¥2,000,000); Fiscal Year 2009: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: 腸管 / 粘膜固有層 / TLR5 / Salmonella typhimurium / Th17

Research Abstract

腸管は食物の吸収や常在細菌叢との共生のため、免疫寛容を誘導する一方で、侵入してくる病原体に対しては免疫反応によって適切に排除を行う。しかしながら、どのような細胞が異物を認識するのか、そしていかにして免疫寛容を凌駕して自然免疫系を活性化するかは全く分かっていなかった。最近、応募者は、自然免疫の代表的な受容体群であるToll-like receptor (TLR)ファミリーの中で、細菌のフラジェリンを認識するTLR5が腸管粘膜固有層の樹状細胞に特異的に発現していることを明らかにした。これらの樹状細胞は脾臓の一般的な樹状細胞とことなり、粘膜特異的なIgA産生や自己免疫疾患の発症に密接に関わると言われているT_H-17細胞の誘導に関わることを明らかにした。本研究課題では、腸管粘膜固有層の樹状細胞によるT_H-17細胞誘導のメカニズムや感染防御における役割、またこの樹状細胞によって誘導される抗原特異的なIgAがSalmonella typhimurium感染においてどのような役割を果たすかを検討する。腸管粘膜固有層に存在するCD11c^<hiCD11b^<hi>樹状細胞を腸管から単離して、CpG DNA存在下に抗原を取り込ませ、マウスの腹腔内に投与して免疫をした。免疫マウスの腸管では、血清中に抗原特異的なIgG産生及び糞便中に抗原特異的なIgA産生を認めた。また、脾臓には抗原特異的なTh1細胞やTh17細胞が誘導され、さらに強い抗原特異的な細胞傷害活性が認められた。以上のことから、腸管粘膜固有層に存在するCD11c^<hi>CD11b^<hi>の樹状細胞はTh1応答とIgG産生のみならず、腸管粘膜面でのIgA産生、Th17応答そして強い細胞傷害活性を誘導出来ることから、粘膜ワクチンの標的として至適な細胞であることが明らかになった。

Research Products

• [Journal Article] Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure. (2011)
  • Author(s): Paveglio SA, Allard J, Foster Hodgkins SR, Ather JL, Bevelander M, Campbell JM, Whittaker LeClair LA, McCarthy SM, van der Vliet A, Suratt BT, Boyson JE, Uematsu S, Akira S, Poynter ME.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: 44(1) Pages: 11-23
  • Peer Reviewed
• [Journal Article] TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. (2011)
  • Author(s): Letran SE, Kee SJ, Atif SM, Uematsu S, Akira S, McSorley SJ.
  • Journal Title: Eur J Immunol. Volume: 41(1) Pages: 29-38
  • Peer Reviewed
• [Journal Article] Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis. (2010)
  • Author(s): Fong DJ, Hogaboam, CM, Matsuno Y, Akira S, Uematsu S, Joshi AD.
  • Journal Title: Immunology. Volume: 130(1) Pages: 125-136
  • Peer Reviewed
• [Journal Article] Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-kappa B signaling. (2010)
  • Author(s): Toma C, Higa N, Koizumi Y, Nakasone N, Ogura Y, McCoy AJ, Franchi L, Uematsu S, Sagara J, Taniguchi S, Tsutsui H, Akira S, Tschopp J, Nunez G, Suzuki T.
  • Journal Title: J Immunol. Volume: 184(9) Pages: 287-297
  • Peer Reviewed
• [Journal Article] Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells. (2010)
  • Author(s): Pan ZJ, Maier S, Schwarz K, Azbill J, Akira S, Uematsu S, Farris AD.
  • Journal Title: Ann Rheum Dis. Volume: 69(6) Pages: 1195-1199
  • Peer Reviewed
• [Journal Article] Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice. (2010)
  • Author(s): Santiago-Raber ML, Dunand-Sauthier I, Wu T, Li QZ, Uematsu S, Akira S, Reith W, Mohan C, Kotzin BL, Izui S.
  • Journal Title: J Autoimmun. Volume: 34(4) Pages: 339-348
  • Peer Reviewed
• [Journal Article] mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice. (2010)
  • Author(s): Kamata H, Hosono K, Suzuki T, Ogawa Y, Kubo H, Katoh H, Ito Y, Uematsu S, Akira S, Watanabe M, Majima M.
  • Journal Title: Biomed Pharmacother. Volume: 4(6) Pages: 409-416
  • Peer Reviewed
• [Journal Article] Pathways regulating cytosolic phospholipase A2 activation and eicosanoid production in macrophages by Candida albicans. (2010)
  • Author(s): Suram S, Gangelhoff TA, Taylor PR, Rosas M, Brown GD, Bonventre JV, Akira S, Uematsu S, Williams DL, Murphy RC, Leslie CC.
  • Journal Title: J Biol Chem. Volume: 285(40) Pages: 30676-30685
  • Peer Reviewed
• [Journal Article] Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers. (2010)
  • Author(s): Ae T, Ohno T, Hattori Y, Suzuki T, Hosono K, Minamino T, Sato T, Uematsu S, Akira S, Koizumi W, Majima M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 299(5)
  • Peer Reviewed
• [Journal Article] Apolipoprotein CIII induces monocyte chemoattractant protein-1 and interleukin 6 expression via Toll-like receptor 2 pathway in mouse adipocytes. (2010)
  • Author(s): Abe Y, Kawakami A, Osaka M, Uematsu S, Akira S, Shimokado K, Sacks FM, Yoshida M.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 30(11) Pages: 2242-2248
  • Peer Reviewed
• [Journal Article] Role of adrenomedullin in Lyme disease. (2010)
  • Author(s): Marre ML, Darcy CT, Yinh J, Akira S, Uematsu S, Steere AC, Hu LT.
  • Journal Title: Infect Immun. Volume: 78(12) Pages: 307-313
  • Peer Reviewed
• [Journal Article] The innate immune system in the intestine. (2010)
  • Author(s): Uematsu S, Fujimoto K.
  • Journal Title: Microbiol Immunol. Volume: 54(11) Pages: 645-657
  • NAID: 10029546046
  • Peer Reviewed
• [Journal Article] Pivotal Advance : Toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis. (2009)
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  • Journal Title: J Leukoc Biol. 85(4) Pages: 595-605
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• [Journal Article] Induction of adaptive immunity by flagellin does not require robust a ctivation of innate immunity. (2009)
  • Author(s): Sanders CJ, et al
  • Journal Title: Eur J Immunol. 39(2) Pages: 359-371
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• [Journal Article] Toll-like receptor 2 deficiency is associated with enhanced severity of group B streptococcal disease. (2009)
  • Author(s): Puliti M, et al
  • Journal Title: Infect Immun 77(4) Pages: 1524-1531
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• [Journal Article] Bacterial endotoxin induces the release of high mobility group box 1 via the IFN-beta signaling pathway. (2009)
  • Author(s): IKim JH, et al
  • Journal Title: J Immunol. 182(4) Pages: 2458-2466
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• [Journal Article] Th2 allergic immune response to inhaled fungal antigens is modulated by TLR-4-independent bacterial products. (2009)
  • Author(s): Allard JB, et al
  • Journal Title: Eur J Immunol. 39(3) Pages: 776-788
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• [Journal Article] Toll-like receptor 3 enhances late-phase reaction of experimental allergic conjunctivitis. (2009)
  • Author(s): Ueta M, et al
  • Journal Title: J Allergy Clin Immunol 123(5) Pages: 1587-9156
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• [Journal Article] Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin. (2009)
  • Author(s): Janot L, et al
  • Journal Title: Eur J Immunol. 39(6) Pages: 1587-1596
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• [Journal Article] Baculovirus induces type I interferon production through toll-like receptor-dependent and -independent pathways in a cell-type-specific manner. (2009)
  • Author(s): Abe T, et al
  • Journal Title: J Virol 83(15) Pages: 7629-7640
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• [Journal Article] Direct stimulation of tlr5+/+ CD11c+ cells is necessary for the adjuvant activity of flagellin. (2009)
  • Author(s): Bates JT, et al
  • Journal Title: J Immunol. 182(12 Pages: 7539-7547
  • Peer Reviewed
• [Journal Article] Polyl : C-induced reduction in uptake of soluble antigen is independent of dendritic cell activation. (2009)
  • Author(s): Tirapu I, et al
  • Journal Title: Int Immunol. 21(7) Pages: 871-879
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• [Journal Article] Downstream signals for MyD88-mediated phagocytosis of Borrelia burgdorferi can be initiated by TRIF and are dependent on PI3K. (2009)
  • Author(s): Shin OS, et al
  • Journal Title: J Immunol. 183(1) Pages: 491-498
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• [Journal Article] NFATc1 mediates Toll-like receptor-independent innate immune responses during Trypanosoma cruzi infection. (2009)
  • Author(s): Kayama H, et al
  • Journal Title: PLoS Pathog. 5(7)
  • Peer Reviewed
• [Journal Article] Endothelial microsomal prostaglandin E synthase-1 exacerbates neuronal loss induced by kainate. (2009)
  • Author(s): Takemiya T, et al
  • Journal Title: J Neurosci Res. 88(2) Pages: 381-390
  • Peer Reviewed
• [Presentation] Antigen-specific cytokine profiles and phenotypes in small intestinal Th17 cells. (2010)
  • Author(s): 植松智
  • Organizer: 第10回淡路島感染症免疫フォーラム
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫)
• [Presentation] 特別講演 臨床医が知っておきたい自然免疫の知識-基本から最近の知見まで- (2009)
  • Author(s): 植松智
  • Organizer: 第149回大阪小児科医会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-09-12
• [Presentation] 特別講演 自然免疫と消化管 (2009)
  • Author(s): 植松智
  • Organizer: 第23回大阪小児栄養消化器病懇話会
  • Place of Presentation: 大阪
  • Year and Date: 2009-06-06
• [Presentation] Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. (2009)
  • Author(s): Uematsu S
  • Organizer: The 2009 Fall Conference of The Korean Association of Immunologists.
  • Place of Presentation: ソウル市(韓国)
• [Book] 臨床粘膜免疫学 粘膜における自然免疫 TLRs・RLRs. (2010)
  • Author(s): 植松智, 審良静男
  • Publisher: シナジー
• [Book] 臨床粘膜免疫学 分泌型IgA誘導における分子・細胞環境 粘膜系樹状細胞(実行組織) (2010)
  • Author(s): 植松智
  • Publisher: シナジー
• [Remarks]
  • URL: http://hostdefense.ifrec.osaka-u.ac.jp/ja/members/uematsu.html
• [Remarks]
  • URL: http://hostedfense.ifrec.osaka-u.ac.jp/ja/members/uematsu.html