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Open Access Research article

CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls

Xiangli Li12, Blair U Bradford3, Frederick Dalldorf4, Sanna M Goyert5, Stephen A Stimpson6, Ronald G Thurman3 and Sergei S Makarov278*

Author Affiliations

1 Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

2 Thurston Arthritis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

4 Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

5 Division of Molecular Medicine, North Shore University Hospital, Cornell University Medical College, Manhasset, New York, USA

6 GlaxoSmithKline, Research Triangle Park, North Carolina, USA

7 Department of Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

8 Comprehensive Center for Inflammatory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

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Arthritis Res Ther 2004, 6:R273-R281  doi:10.1186/ar1175

Published: 27 April 2004

Abstract

Bacterial infections play an important role in the multifactorial etiology of rheumatoid arthritis. The arthropathic properties of Gram-positive bacteria have been associated with peptidoglycan–polysaccharide complexes (PG-PS), which are major structural components of bacterial cell walls. There is little agreement as to the identity of cellular receptors that mediate innate immune responses to PG-PS. A glycosylphosphatidylinositol-linked cell surface protein, CD14, the lipopolysaccharide receptor, has been proposed as a PG-PS receptor, but contradictory data have been reported. Here, we examined the inflammatory and pathogenic responses to PG-PS in CD14 knockout mice in order to examine the role for CD14 in PG-PS-induced signaling. We found that PG-PS-induced responses in vitro, including transient increase in intracellular calcium, activation of nuclear factor-κB, and secretion of the cytokines tumor necrosis factor-α and interleukin-6, were all strongly inhibited in CD14 knockout macrophages. In vivo, the incidence and severity of PG-PS induced acute polyarthritis were significantly reduced in CD14 knockout mice as compared with their wild-type counterparts. Consistent with these findings, CD14 knockout mice had significantly inhibited inflammatory cell infiltration and synovial hyperplasia, and reduced expression of inflammatory cytokines in PG-PS arthritic joints. These results support an essential role for CD14 in the innate immune responses to PG-PS and indicate an important role for CD14 in PG-PS induced arthropathy.

Keywords:
bacterial; cell surface molecules; rheumatoid arthritis; transcription factors