The mechanism of innate inflammation in response to cell death and it's contribution to the pathogenesis of rheumatoid arthritis

• Project/Area Number: 23591468
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Teikyo University
• Principal Investigator: KONO Hajime 帝京大学, 医学部, 准教授 (60585074)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 自然炎症 / IL-1 / Cathepsin C / Caspase 1 / 細胞死 / インフラマソーム / 結晶 / 自然免疫 / 炎症

Research Abstract

Cell death, especially necrotic cell death, induces acute inflammation. It is supposed that this acute responses underlie many pathological conditions including autoimmune diseases, but the molecular mechanisms of the danger signals to evoke inflammation or the key pathways responsible for neutrophil recruitment are not well studied.
We investigated the molecular mechanisms responsible for inducing inflammatory responses to necrotic cells in vivo. In our system the inflammation to cell death depends on IL-1. IL-1 is transcribed as an immature protein and requires cleavage by Caspase-1. Here we identified a novel molecular pathway to cell death-induced inflammation that is dependent on IL-1, but not on Caspase-1. IN addition, we identified Cathepsin C as one of the key molecules involved in this Caspase-1 independent pathway in vivo. Cathepsin C is known to maturate neutrophil serene proteases including proteinase 3 that was shown to have ability to maturate IL-1 in vitro.

Research Products

• [Journal Article] Molecular determinants of sterile inflammation (2014)
  • Author(s): Kono H, Onda A, Yanagida T
  • Journal Title: Curr Opin Immunol Volume: (Epub 2014 Jan 7) Pages: 147-56
  • DOI: 10.1016/j.coi.2013.12.004
  • Peer Reviewed
• [Journal Article] Human leukocyte antigens and systemic lupus erythematosus: A protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03 (2014)
  • Author(s): Furukawa H, Kawasaki A, Oka S, Ito I, Shimada K, Sugii S, Hashimoto A, Komiya A, Fukui N, Kondo Y, Ito S, Hayashi T, Matsumoto I, Kusaoi M, Amano H, Nagai T, Hirohata S, Setoguchi K, Kono H, Okamoto A, Chiba N, Suematsu E, Katayama M, Migita K, Suda A, Ohno S, Hashimoto H, Takasaki Y, Sumida T, Nagaoka S, Tsuchiya N, Tohma S
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: 152-160
  • DOI: 10.1371/journal.pone.0087792
  • URL: https://pure.teikyo.jp/en/publications/013d1a26-bb79-4ec8-9df6-def47801b1d7
  • Peer Reviewed / Open Access
• [Journal Article] High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3 (2014)
  • Author(s): De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald ML, Hernandez NJ, Williams BR, Knolle P, Kneilling M, Röcken M, Lütjohann D, Wright SD, Schultze JL, Latz E
  • Journal Title: Nat Immunol Volume: 15(2)(Epub 2013 Dec 8) Issue: 2 Pages: 152-60
  • DOI: 10.1038/ni.2784
  • Peer Reviewed / Open Access
• [Journal Article] In vivo evaluation of neutrophil recruitment in response to sterile particulates (2013)
  • Author(s): Tamiko Yanagida, Kaoru Orihashi, Hajime Kono
  • Journal Title: Methods in Molecular Biology (Clifton, N.J.) Volume: 1040 Pages: 211-221
  • DOI: 10.1007/978-1-62703-523-1_16
  • ISBN: 9781627035224, 9781627035231
  • URL: https://pure.teikyo.jp/en/publications/08c4bf06-c9d0-4886-aca6-2259ba7fe2bd
  • Peer Reviewed
• [Journal Article] The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C (2012)
  • Author(s): Kono H, Orlowski GM, Patel Z, Rock KL
  • Journal Title: J Immunol Volume: 189(7)(Epub 2012 Aug 22) Pages: 3734-40
  • Peer Reviewed
• [Journal Article] The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C (2012)
  • Author(s): Kono H, Orlowski GM, Patel Z, Rock KL.
  • Journal Title: Journal of Immunology Volume: 189 Issue: 7 Pages: 3734
  • DOI: 10.4049/jimmunol.1200136
  • URL: https://pure.teikyo.jp/en/publications/7cf81252-d753-4f64-8686-943986bd5935
  • Peer Reviewed
• [Journal Article] 動脈硬化と自然免疫 (2012)
  • Author(s): 河野肇
  • Journal Title: Annual Reviews循環器2012 Volume: 2012 Pages: 42-48
• [Journal Article] Innate and adaptive immune responses to cell death (2011)
  • Author(s): Rock KL, Lai JJ, Kono H
  • Journal Title: Immunological Reviews Volume: 243 Issue: 1 Pages: 191
  • DOI: 10.1111/j.1600-065x.2011.01040.x
  • URL: https://pure.teikyo.jp/en/publications/9b3b521f-6efd-4f04-9540-dd401fce3706
  • Peer Reviewed
• [Journal Article] Innate and adaptive immune reponses to cell death. (2011)
  • Author(s): Rock KL, Lai JJ, Kono H
  • Journal Title: Immunol Rev Volume: 243 Pages: 191-205
  • Peer Reviewed
• [Journal Article] NLRPインフラマソームと動脈硬化 (2011)
  • Author(s): 河野肇
  • Journal Title: 呼吸と循環 Volume: 59 Pages: 873-882
• [Presentation] BEYOND THE INFLAMMASOME: ROLE OF DIPEPTIDYL PEPTIDASE I (CATEPSIN C) IN THE MATURATION OF IL-1Β IN VIVO (2011)
  • Author(s): Hajime Kono
  • Organizer: Annual European Congress of Rheumatology EULAR 2011
  • Place of Presentation: London, UK
• [Presentation] The IL-1-dependent sterile inflammatory response has a substantial caspase-1- independent domponent that requires cathepsin C
  • Author(s): H. Kono, G. Orlowski, Z .Patel, K. L. Rock
  • Organizer: IEIIS 2012
  • Place of Presentation: Tokyo
• [Presentation] インフラマソーム非依存性IL-1β活性化による結晶誘発性急性炎症
  • Author(s): 河野 肇、柳田 たみ子、浅子 来美、高山 真希、菊地 弘敏
  • Organizer: 第57回日本リウマチ学会総会
  • Place of Presentation: 京都