期刊
ARTHRITIS AND RHEUMATISM
卷 62, 期 11, 页码 3353-3364出版社
WILEY
DOI: 10.1002/art.27654
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资金
- European Union
- Dutch Arthritis Association [07-2-301]
Objective. The levels of both Fc gamma receptor (Fc gamma R) and the alarmins S100A8 and S100A9 are correlated with the development and progression of cartilage destruction during antigen-induced arthritis (AIA). This study was undertaken to study the active involvement of S100A8, S100A9, and S100A8/S100A9 in Fc gamma R regulation in murine macrophages and synovium during AIA. Methods. Recombinant murine S100A8 (rS100A8) was injected into normal mouse knee joints, and the synovium was isolated for analysis of Fc gamma R messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR). Macrophages, including bone marrow macrophages derived from Toll-like receptor 4-deficient (TLR-4(-/-)) mice, and polymorphonuclear cells (PMNs) were stimulated with S100 proteins, and levels of Fc gamma R mRNA and protein were measured using RT-PCR and fluorescence-activated cell sorting analyses. AIA was induced in the knee joints of S100A9-deficient (S100A9(-/-)) mice, compared with wild-type (WT) controls, and the extent of cartilage destruction was determined using immunohistochemical analysis. Results. Intraarticular injection of rS100A8 into the knee joints of normal mice caused a strong up-regulation of mRNA levels of activating Fc gamma RI (64-fold increase) and Fc gamma RIV (256-fold increase) in the synovium. Stimulation of macrophages with rS100A8 led to significant up-regulation of mRNA and protein levels of Fc gamma RI and Fc gamma RIV, but not Fc gamma RIII, while the effects of S100A9 or S100A8/S100A9 complexes were less potent. Stimulation of PMNs (32Dcl3 cell line) with S100 proteins had no effect on Fc gamma R expression. Up-regulation of Fc gamma RI and Fc gamma RIV was abrogated in rS100A8-stimulated macrophages from TLR-4(-/-) mice, indicating that the induction of Fc gamma R expression by S100A8 is mediated by TLR-4. Fc gamma R expression in the inflamed synovium of S100A9(-/-) mice was significantly lower on day 14 after arthritis induction when compared with WT controls, and these findings correlated with reduced severity of matrix metalloproteinase-mediated cartilage destruction. Conclusion. S100A8 is a strong promoter of activating Fc gamma RI and Fc gamma RIV in macrophages through the activation of TLR-4, and acts as a regulator of Fc gamma R expression in inflamed synovium in chronic experimental arthritis.
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