title: An inflammation loop orchestrated by S100A9 and calprotectin is critical for development of arthritis.
abstract: OBJECTIVE
  The S100A9 and S100A8 proteins are highly expressed by neutrophils and monocytes and are part of a group of damage-associated molecular pattern molecules that trigger inflammatory responses. Sera and synovial fluids of patients with rheumatoid arthritis (RA) contain high concentrations of S100A8/A9 that correlate with disease activity.
  
  
  METHODS
  In this study, we investigated the importance of S100A9 in RA by using neutralizing antibodies in a murine lipopolysaccharide-synchronized collagen-induced arthritis model. We also used an in vitro model of stimulation of human immune cells to decipher the role played by S100A9 in leukocyte migration and pro-inflammatory cytokine secretion.
  
  
  RESULTS
  Treatment with anti-S100A9 antibodies improved the clinical score by 50%, diminished immune cell infiltration, reduced inflammatory cytokines, both in serum and in the joints, and preserved bone/collagen integrity. Stimulation of neutrophils with S100A9 protein led to the enhancement of neutrophil transendothelial migration. S100A9 protein also induced the secretion by monocytes of proinflammatory cytokines like TNFα, IL-1β and IL-6, and of chemokines like MIP-1α and MCP-1.
  
  
  CONCLUSIONS
  The effects of anti-S100A9 treatment are likely direct consequences of inhibiting the S100A9-mediated promotion of neutrophil transmigration and secretion of pro-inflammatory cytokines from monocytes. Collectively, our results show that treatment with anti-S100A9 may inhibit amplification of the immune response and help preserve tissue integrity. Therefore, S100A9 is a promising potential therapeutic target for inflammatory diseases like rheumatoid arthritis for which alternative therapeutic strategies are needed.
authors.affiliation: Centre de recherche en Infectiologie, Centre de recherche du Centre Hospitalier Universitaire de Quebec, and Faculty of Medecine, Université Laval, Quebec, Canada.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Cesaro
authors.forename: Nadia
authors.initials: N
authors.lastname: Anceriz
authors.forename: Audrey
authors.initials: A
authors.lastname: Plante
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pagé
authors.forename: Mélanie R
authors.initials: MR
authors.lastname: Tardif
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Tessier
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001842:Bone and Bones / Q000473:pathology; D040502:Calgranulin B / Q000276:immunology* / Q000378:metabolism; D002356:Cartilage / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D040502:Calgranulin B; D016207:Cytokines; D018836:Inflammation Mediators; D039841:Leukocyte L1 Antigen Complex; D014409:Tumor Necrosis Factor-alpha