Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID Mice.
OBJECTIVE
The mechanisms by which monocyte/macrophage cells migrate to the joint involve a series of integrated adhesion and signaling events in which chemokines and their receptors are strongly implicated. This study was undertaken to investigate the hypothesis that stromal cell-derived factor 1 (SDF-1), a CXC chemokine (CXCL12), plays a critical role in monocyte/macrophage localization to synovium.


METHODS
SDF-1 and CXC receptor 4 (CXCR4) expression in rheumatoid arthritis (RA) and osteoarthritis synovium and graft SDF-1, tumor necrosis factor alpha (TNF alpha), and human and murine vascular markers were examined by immunohistochemistry and double-immunofluorescence. The functional capacity of SDF-1 to modulate monocyte migration into joints was investigated by examining the localization of pro-myelomonocytic U937 cells into synovial tissue transplanted into SCID mice. SDF-1, TNF alpha, or saline was injected into graft sites and response determined by the number of fluorescently labeled U937 cells (injected intravenously) detected in grafts by ultraviolet microscopy.


RESULTS
SDF-1 and CXCR4 were highly expressed in CD68+ cells in the RA synovium. SDF-1 induced U937 cell migration in vitro and in vivo in a dose-dependent manner and, in vivo, SDF-1 was more effective than TNF alpha. In contrast to TNF alpha, SDF-1 did not induce intracellular adhesion molecule 1 in transplant microvasculature. Furthermore, intragraft injection of SDF-1 did not up-regulate TNF alpha, or vice versa.


CONCLUSIONS
This study demonstrates, for the first time, that SDF-1 is functional in vivo when injected into synovial grafts. In addition, SDF-1 is more potent than TNF alpha, and its mechanisms of action appear to be autonomous. Therefore, SDF-1 may be an important TNF-independent molecule involved in the migration to and retention of inflammatory effector cells in the joint.
Blades
M C
MC
Guy's, St Thomas and King's College School of Medicine, London, UK.
Ingegnoli
F
F
Wheller
S K
SK
Manzo
A
A
Wahid
S
S
Panayi
G S
GS
Perretti
M
M
Pitzalis
C
C
D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013583:Synovial Membrane / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology* / Q000637:transplantation*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D018799:Intercellular Adhesion Molecule-1; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse