Increased expression of fractalkine (CX3CL1) and its receptor, CX3CR1, in Wegener's granulomatosis--possible role in vascular inflammation.
OBJECTIVE
Based on the function of fractalkine (CX3CL1), the unique member of the CX3C chemokine subfamily, in endothelial-related inflammation, we hypothesized a role for CX3CL1 and its receptor (CX3CR) in Wegener's granulomatosis (WG). In the present study, this hypothesis was tested by different experimental approaches.


METHODS
We examined plasma levels of CX3CL1 (enzyme immunoassay) and CX3CR1 expression in peripheral blood mononuclear cells (PBMCs) (real-time quantitative RT-PCR and flow cytometry) in 18 WG patients and 15 healthy controls. In eight of these individuals, we also examined CX3CR1-mediated chemotaxis and adhesion in T cells and monocytes as well as the effects of CX3CL1 on monocyte chemoattractant protein (MCP) 1 levels in PBMC supernatants.


RESULTS
Our main findings were: (i) WG patients had markedly increased plasma levels of CX3CL1, with particularly high levels in those with active disease, (ii) These increased CX3CL1 levels were accompanied by enhanced expression of its corresponding receptor, CX3XR1, in PBMC, primarily reflecting an increased proportion of CX3CR1(+)CD3(+)CD4(+) T cells and (iii) The up-regulation of CX3CR1 in PBMC from WG patients affected their functional potential as shown by CX3CL1-induced enhancement of chemotaxis, adhesion, responses as well as MCP-1 stimulation.


CONCLUSIONS
Based on the ability of CX3CL1 to promote leucocyte infiltration into the vessel wall of inflammatory levels, it is tempting to hypothesize that increased CX3CL1/CX3CR1 interaction could be involved in the pathogenesis of the granulomatous vasculitis characterizing WG.
Bjerkeli
Vigdis
V
Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, 0027 Oslo, Norway. vigdis.bjerkeli@medisin.uio.no
Damås
Jan Kristian
JK
Fevang
Børre
B
Holter
Jan Cato
JC
Aukrust
Pål
P
Frøland
Stig S
SS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000097:blood*; D002634:Chemotaxis, Leukocyte; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000097:blood* / Q000276:immunology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000097:blood*; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology
C111835:CCL2 protein, human; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D008565:Membrane Proteins; D019707:Receptors, Chemokine