Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints.
OBJECTIVE
Directional migration of leukocytes is orchestrated by the regulated expression of chemokine receptors and their ligands. The receptor CXCR6 is abundantly expressed by Th1-polarized effector/memory lymphocytes accumulating at inflammatory sites. This study was undertaken to examine the presence of CXCR6+ T cells and of CXCL16, the only ligand for CXCR6, in the joints of patients with rheumatoid arthritis (RA).


METHODS
Flow cytometry analysis of the expression of CXCR6 by peripheral blood and synovial fluid (SF) T cells. In addition, by performing conventional and real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay, we determined the expression of CXCL16 and its protease ADAM-10 within synovium and by cultured macrophages. SF T cell migration was studied with the Transwell system.


RESULTS
Accumulation of CXCR6+ T cells within RA SF coincided with highly elevated levels of CXCL16+ macrophages. In vitro studies revealed that monocytes started to express CXCL16 upon differentiation into macrophages, and that RA SF and tumor necrosis factor (TNF) enhanced CXCL16 expression. Moreover, RA patients responding to anti-TNF therapy showed a strongly decreased CXCL16 expression, whereas nonresponding patients did not. Interestingly, ADAM-10, a recently identified protease of CXCL16, was abundantly expressed by CXCL16+ macrophages in vitro and in RA in vivo, which resulted in increased levels of cleaved CXCL16 in RA SF relative to controls. Finally, CXCR6+ T cells from RA SF were attracted by CXCL16.


CONCLUSIONS
These data provide evidence that enhanced production of CXCL16 in RA synovia leads to recruitment of CXCR6+ memory T cells, thereby contributing to the inflammatory cascade associated with RA pathology.
van der Voort
Robbert
R
Nijmegen Center for Molecular Life Sciences, University Medical Center St. Radboud, Nijmegen, The Netherlands.
van Lieshout
Antoine W T
AW
Toonen
Liza W J
LW
Slöetjes
Annet W
AW
van den Berg
Wim B
WB
Figdor
Carl G
CG
Radstake
Timothy R D J
TR
Adema
Gosse J
GJ
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000096:biosynthesis*; D006801:Humans; D007156:Immunologic Memory; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis*; D008666:Metalloendopeptidases / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D051116:Receptors, Scavenger; D013582:Synovial Fluid / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human