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

2013 Fiscal Year Final Research Report

• 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
• Keywords: 自然炎症 / IL-1 / Cathepsin C / Caspase 1

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(2)(eCollection 2014) Pages: e87792
  • DOI: 10.1371/journal.pone.0087792
  • Peer Reviewed
• [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) Pages: 152-60
  • DOI: 10.1038/ni.2784
  • Peer Reviewed
• [Journal Article] In vivo evaluation of neutrophil recruitment in response to sterile particulates (2013)
  • Author(s): Yanagida T, Orihashi K, Kono H
  • Journal Title: Methods Mol Biol Volume: 1040 Pages: 211-21
  • DOI: 10.1007/978-1-62703-523-1_16
  • 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] Innate and adaptive immune responses to cell death,Review (2011)
  • Author(s): Rock KL, Lai JJ, Kono H
  • Journal Title: Immunol Rev Volume: 243(1) Pages: 191-205
  • DOI: 10.1111/j.1600-065X.2011.01040.x
  • Peer Reviewed
• [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