Expression of the dendritic cell-associated C-type lectin DC-SIGN by inflammatory matrix metalloproteinase-producing macrophages in rheumatoid arthritis synovium and interaction with intercellular adhesion molecule 3-positive T cells.
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.


CONCLUSIONS
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.
van Lent
Peter L E M
PL
Department of Rheumatology, University Medical Centre Nijmegen, Nijmegen, The Netherlands. P.vanlent@reuma.azn.nl
Figdor
Carl G
CG
Barrera
Pilar
P
van Ginkel
Karin
K
Slöetjes
Annet
A
van den Berg
Wim B
WB
Torensma
Ruurd
R
D015703:Antigens, CD / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D000097382:CD68 Molecule
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D020781:Matrix Metalloproteinase 1; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C483616:ICAM3 protein, human