OBJECTIVE: To determine whether matrix metalloproteinase (MMP)-producing inflammatory macrophages in the synovium of rheumatoid arthritis (RA) patients express the novel dendritic cell (DC)-specific C-type lectin DC-SIGN and whether this expression is associated with the presence of naive T cells expressing the DC-SIGN ligand, intercellular adhesion molecule 3 (ICAM-3). METHODS: Reverse transcription-polymerase chain reaction was performed to study the expression of DC-SIGN in synovium samples from RA, osteoarthritis (OA), and trauma patients. DC-SIGN expression on RA monocytes or on monocytes stimulated with granulocyte-macrophage colony-stimulating factor and interleukin-4 was further investigated by flow cytometry. To localize DC-SIGN in the synovium, the DC markers ICAM-3 and MMP-1 were analyzed by immunohistochemistry (single and double labeling) on serial cryostat sections. RESULTS: Seventy percent of the inflammatory cells in the synovium of RA patients showed high expression of DC-SIGN. DC-SIGN was expressed by 80% of CD68-positive macrophages, but not by CD83-positive, DC-LAMP-positive, or Fascin-positive cells. Normal numbers of DC-SIGN-positive cells were found in the peripheral blood of RA patients, suggesting that DC-SIGN is up-regulated locally in the joint. In RA synovium, ICAM-3-positive resting T cells were found in close proximity to DC-SIGN cells. Unexpectedly, a lower percentage of DC-SIGN-expressing cells was found in OA synovium compared with RA synovium. Furthermore, ICAM-3-expressing T cells, which are known to bind DC-SIGN, were almost absent within the synovium of OA and trauma patients. DC-SIGN-positive macrophages adjacent to these T cells were located in close proximity to the cartilage-degrading proteins extracellular MMP inducer (EMMPRIN) and MMP-1. CONCLUSION: The C-type lectin DC-SIGN is almost absent in the synovium of trauma patients but is highly expressed by most CD68-positive macrophages in the synovium of RA patients. The lack of correlation between DC-SIGN expression and the expression of CD83, DC-LAMP, or Fascin indicates that multiple DC/macrophage subsets are present in RA synovium. Expression of DC-SIGN and its ligand, ICAM-3, is found in substantial amounts only in RA synovium, suggesting that their interaction is implicated in the additional activation of synovial macrophages that leads to the production of EMMPRIN and MMP-1.