A new host-pathogen interaction in arthritis

• 
  Project Lead
  Dr Andrew Fleetwood

  andrew.fleetwood@unimelb.edu.au

  View researcher's webpage

  +61 8344 3299

Project Details

Emerging clinical evidence implicates the oral microbiome, specifically P.gingivalis, as a potential factor in arthritis pathogenesis. We recently found that the P.gingivalis-derived gingipain Kgp cleaves latent pro-uPA to active uPA.

Activated uPA can initiate a proteolytic cascade, which we have shown is required for disease in experimental arthritis and periodontal disease models. Therefore we are investigating whether P.gingivalis exacerbation of experimental arthritis and periodontal disease is dependent on Kgp gingipain-induced activation of the host uPA proteolytic cascade.

This mechanism may allow the pathogen to directly activate a major destructive host pathway to promote tissue and bone destruction, which are two of the clinical hallmarks of rheumatoid arthritis.

Researchers

• Andrew Fleetwood, Project Leader
• Prof John Hamilton
• Adrian Achuthan, Research Fellow
• A/Prof Andrew Cook

Collaborators

• A/Prof Neil O'Brien-Simpson
• Prof Stuart Dashper
• Prof Eric Reynolds

Funding

• NHMRC Project Grant (ID 1107001).

Research Outcomes

1. Fleetwood AJ, O'Brien-Simpson NM, Veith PD, Lam RS, Achuthan A, Cook AD, Singleton W, Lund  IK, Reynolds EC, Hamilton JA. Porphyromonas gingivalis-derived RgpA-Kgp Complex Activates the Macrophage Urokinase Plasminogen Activator System: Implications for Periodontitis. J Biol Chem. 2015 Jun 26;290(26):16031-42.
2. Lam RS, O'Brien-Simpson NM, Hamilton JA, Lenzo JC, Holden JA, Brammar GC, Orth RK, Tan Y, Walsh KA, Fleetwood AJ, Reynolds EC. GM-CSF and uPA are required for P. gingivalis-induced alveolar bone loss in a mouse periodontitis model. Immunol Cell Biol. 2015 Sep;93(8):705-15.
3. Fleetwood AJ, Achuthan A, Almholt K, Usher P, Hamilton JA. Urokinase plasminogen activator is a central regulator of macrophage three-dimensional invasion, matrix degradation, and adhesion. J Immunol. 2014 Apr 15;192(8):3540-7.
4. Cook AD, De Nardo CM, Braine EL, Turner AL, Vlahos R, Way KJ, Beckman SK, Lenzo JC, Hamilton JA. Urokinase-type plasminogen activator and arthritis progression: role in systemic disease with immune complex involvement. Arthritis Res Ther. 2010;12(2):R37.
5. De Nardo CM1, Lenzo JC, Pobjoy J, Hamilton JA, Cook AD.Urokinase-type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models. Arthritis Res Ther. 2010;12(5):R199.

Research Publications

1. Schultz HS, Guo L, Keller P, Fleetwood AJ, Hamilton JA, Berchtold MW, Panina S. OSCAR-collagen signaling in monocytes plays a pro-inflammatory role and may contribute to the pathogenesis of rheumatoid arthritis.Eur J Immunol. 2016 Apr;46(4):952-63.
2. Louis C, Cook AD, Lacey D, Fleetwood AJ, Vlahos R, Anderson GP, Hamilton JA. Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System. J Immunol. 2015 Jul 1;195(1):134-44.
3. Schultz HS, Nitze LM, Zeuthen LH, Keller P, Gruhler A, Pass J, Chen J, Guo L, Fleetwood AJ, Hamilton JA, Berchtold MW, Panina S. Collagen induces maturation of human monocyte-derived dendritic cells by signaling through osteoclast-associated receptor. J Immunol. 2015 Apr 1;194(7):3169-79.
4. Read CB, Kuijper JL, Hjorth SA, Heipel MD, Tang X, Fleetwood AJ, Dantzler JL, Grell SN, Kastrup J, Wang C, Brandt CS, Hansen AJ, Wagtmann NR, Xu W, Stennicke VW. Cutting Edge: identification of neutrophil PGLYRP1 as a ligand for TREM-1.J Immunol. 2015 Feb 15;194(4):1417-21.