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PLoS One. 2012;7(9):e45478. doi: 10.1371/journal.pone.0045478. Epub 2012 Sep 18.

An inflammation loop orchestrated by S100A9 and calprotectin is critical for development of arthritis.

Author information

1
Centre de recherche en Infectiologie, Centre de recherche du Centre Hospitalier Universitaire de Quebec, and Faculty of Medecine, Université Laval, Quebec, Canada.

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.

CONCLUSION:

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.

PMID:
23029038
PMCID:
PMC3445527
DOI:
10.1371/journal.pone.0045478
[Indexed for MEDLINE]
Free PMC Article

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