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Rheumatology Advance Access originally published online on July 6, 2007
Rheumatology 2007 46(9):1422-1427; doi:10.1093/rheumatology/kem168
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Increased expression of fractalkine (CX3CL1) and its receptor, CX3CR1, in Wegener's granulomatosis—possible role in vascular inflammation

V. Bjerkeli1, J. K. Damås1,2, B. Fevang1, J. C. Holter2, P. Aukrust1,2 and S. S. Frøland1,2

1Research Institute for Internal Medicine, Faculty Division Rikshospitalet, University of Oslo and 2Section of Clinical Immunology and Infectious Diseases, Medical Department, Rikshospitalet-Radiumhospitalet Medical Center and Faculty Division Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.

Correspondence to: Vigdis Bjerkeli, Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, 0027 Oslo, Norway. E-mail: vigdis.bjerkeli{at}medisin.uio.no


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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.

Conclusion. 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.

KEY WORDS: Wegener's granulomatosis, Fractalkine, Chemokines, Inflammation, Mononuclear cells


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Wegener's granulomatosis (WG) is a necrotizing, granulomatous vasculitis belonging to the small- to medium-sized vessel systemic vasculitides. Although, usually affecting the upper airways, lungs and kidneys, WG is a multi-system disease, and the mortality is high without specific therapy [1, 2]. The pathogenesis of WG has not been fully clarified, but seems to involve enhanced leucocyte and endothelial cell activation with increased infiltration of activated leucocytes into inflamed tissue resulting in granuloma formation vasculitis and tissue destruction [1, 3, 4].

Chemokines, a group of cytokines that attract and activate leucocytes into inflamed tissue, have been associated with the pathogenesis of a number of inflammatory diseases, ranging from atherosclerosis to AIDS [5], and there are also some recent reports suggesting their involvement in WG. For instance, Coulomb-L’Hermine et al. [6] found elevated levels of CC-chemokines in pulmonary WG lesions. Moreover, anti-neutrophil cytoplasmic antibodies (ANCAs), which are believed to influence the development and exacerbation of WG, have been found to induce the expression of interleukin (IL)-8 in monocytes and endothelial cells [7, 8]. Although these and some other findings [9–11] may indicate the involvement of chemokines in WG, the specific role of these chemotactic cytokines in the pathogenesis of this disorder is far from clear.

Fractalkine (CX3CL1) is the unique member of the CX3C chemokine subfamily. In contrast to other chemokines, it exists in two forms, each mediating distinct biological actions [12–14]. The membrane-anchored protein, which is primarily expressed on the inflamed endothelium, serves as an adhesion protein promoting the retention of monocytes and T cells in inflamed tissue. The soluble form resembles more a conventional chemokine and strongly induces chemotaxis. Both chemotaxis and adhesion are mediated by the G protein-coupled receptor CX3CR1. Based on these chemotactic and adhesive properties, CX3CL1 has been thought to play an important role in inflammation, and indeed, accumulating evidence indicates that CX3CL1/CX3CR1 are involved in the pathogenesis of various inflammatory disorders such as glomerulonephritis, rheumatoid arthritis and systemic lupus erythematosus (SLE) [15–18]. At present, however, the literature is virtually devoid of data on the pathogenic role of CX3CL1/CX3CR1 in WG.

Based on its role in endothelial-related inflammation, we hypothesized a role for increased CX3CL1/CX3CR interaction in WG. In the present study, this hypothesis was tested by different experimental approaches including studies in plasma and peripheral blood mononuclear cells (PBMCs) from WG patients.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients and controls
A total of 18 patients, 9 males and 9 females with WG were included in the study (Table 1). All patients fulfilled the American College of Rheumatology 1990 classification criteria and the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis 1994 definition for WG [19]. Fifteen of the patients (83%) had biopsy-confirmed WG with necrotizing vasculitis, granulomatous inflammation or both in one or more organ systems. In the three patients in whom WG was not confirmed histologically, the diagnosis was made on the basis of the typical history, characteristic clinical findings and a positive ANCA test with specificity for proteinase-3 (cANCA). WG patients were classified as having active disease or being in remission based on the Birmingham Vasculitis Activity Score (BVAS) [20] as well as levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). WG patients were classified as having active disease if they had BVAS >10 and CRP >50 mg/l or ESR >30 mm/1 h. For comparison, blood samples were also obtained from 15 sex- and age-matched healthy controls. Written informed consent to blood sampling was obtained from all subjects. The study was conducted according to the ethical guidelines at our hospital, according to the Helsinki Declaration and was approved by the hospital's authorized representative.


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  		TABLE 1. Characteristics of the patients with Wegener's granulomatosis (WG)

 
Blood sampling protocol
Peripheral venous blood was drawn into pyrogen-free tubes with EDTA as anticoagulant. The tubes were immediately immersed in melting ice and centrifuged (1500g for 10 min) within 20 min. All samples were stored at –80°C and defrosted only once.

Isolation of cells
PBMCs were obtained from heparinized blood by Isopaque-Ficoll (Lymphoprep; Nycomed, Oslo, Norway) gradient centrifugation. Further separation of CD14+ monocytes (CD14-labelled magnetic beads; MACS, Milteny Biotec, Bergisch Gladbach, Germany) and CD3+ T cells (negative selection by monodisperse immunomagnetic beads; Dynal, Oslo, Norway) were performed as described elsewhere [21, 22]. The negatively selected T cells consisted of >90% CD3+ cells and the positively selected monocytes of >95% CD14+ cells (flow cytometry).

Cell culture experiments
Freshly isolated PBMCs were resuspended in RPMI 1640 (Gibco, Paisley, UK) with 2 mM L-glutamine and 25 mM HEPES buffer and 5% fetal calf serum (FCS; BioSciences, Buckingham, UK), and seeded in 96-well plates (Costar, Cambridge, MA, USA; 2 x 106 cells/ml, 1 ml/well) with or without CX3CL1 (chemokine domain; R&D Systems, Minneapolis, MN, USA). Cell-free supernatants were harvested after 20 h and stored at –80°C until analysis.

Chemotaxis assay
Chemotactic activities were estimated in 24-well Transwell plates (Costar) using polycarbonate membranes with 8 µm pore size (Falcon; Becton Dickinson Labware, Bedford, MA, USA) as previously described [23]. The lower chamber contained 800 µl RPMI 1640 with 0.5% bovine serum albumin (BSA), 20 mM HEPES, pH 7.4 (buffer A) and human CX3CL1 (chemokine domain full length with a poly-His-tail, R&D Systems) at concentrations known to be chemotactic for T cells and monocytes [23]. To estimate random migration, the chemokine was omitted in negative control experiments. Freshly isolated PBMCs, T cells and monocytes (2.5 x 105/200 µl buffer A) were loaded into the upper chamber, incubated at 37°C for 90 min, and the cells attached to the side of the polycarbonate membrane in contact with the cell suspension were removed. After fixation with 1% formaldehyde, the migrated cells adhering to the underside of the membranes were stained with crystal violet and counted in five high-power fields under an inverted microscope. All experiments were performed in triplicates.

Adhesion assay
96-well plates (Costar) were coated overnight at 4°C with anti-poly-Histidine- antibody (R&D Systems) diluted in phosphate-buffered saline (PBS; 1 : 1000). After two washes with PBS, the wells were blocked with buffer A for 1 h at room temperature. The buffer was removed and CX3CL1 (full length with a poly-His-tail, R&D Systems), diluted in buffer A to a final concentration of 30 nM, was added to each well and incubated for 1 h at room temperature. After two washes with buffer A, freshly isolated PBMCs (2 x 104/100 µl buffer A) were added to each well and incubated for 30 min at 37°C. Unbound cells were washed off (2 x PBS), and bound cells were counted in five high-power fields under an inverted microscope. Uncoated wells were treated in parallel in the absence of anti-poly-His antibody and CX3CL1. All experiments were performed in triplicates.

Real-time quantitative RT-PCR
Total RNA was extracted from PBMCs using RNeasy columns (Qiagen, Hilden, Germany), subjected to DNase I treatment (RQI DNase; Promega, Madison, WI, USA), and stored in RNA storage solution (Ambion, Austin, TX, USA) at –80°C. Primers were designed using the Primer Express software, version 2.0 (Applied Biosystems, Foster City, CA, USA) for CX3CR1 (forward primer: 5'-AARGCCTGGCTGTCCTGTGT-3', reverse primer: 5'-GCCTGCTCCTTTGTGATTCAG-3' and TaqMan probe: 5'-CGCTCAGTCCACGTTGATTTCTCCTCA-3'). Quantification of mRNA was performed using the ABI Prism 7000 (Applied Biosystems) [24]. Gene expression of the housekeeping gene glyceraldehyd-3-phosphate dehydrogenase (GAPDH, Applied Biosystems) was used for normalization.

Flow cytometry
Flow cytometry analyses of freshly isolated PBMCs were performed with the use of phycoerythrin (PE)-conjugated anti-CD14, PE-conjugated anti-CD8, PE-conjugated anti-CD4 and peridinin-chlorophyll-proteincomplex-conjugated (PerCP) anti-CD3 (all from Becton Dickinson Bioscience, San Jose, CA, USA), and fluoresceinisothiocyanate FITC-conjugated anti-CX3CR1 (clone 2A9-1; Medical&Biological Laboratories, Woburn, MA, USA). Nonspecific IgG isotypes were used as negative controls. Flow cytometry was performed using a FACSCalibur instrument with Cell Quest software (Becton Dickinson). List mode files were collected for 50 000 cells from each sample.

Enzyme immunoassays (EIAs)
The soluble form of CX3CL1 and the protein levels of monocyte chemoattractant protein (MCP)-1 were detected by EIAs obtained from R&D Systems.

Statistical analysis
For comparison of two groups, the Mann–Whitney U-test (two-tailed) was used. For comparison within the same individuals, the Wilcoxon matched-pairs test was used. Coefficients of correlation were calculated by the Spearman rank test. Probability values are two-sided and considered significant when <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Plasma levels of CX3CL1 in WG patients and healthy controls
As shown in Fig. 1A, WG patients (n = 18) had significantly raised plasma levels of CX3CL1 compared with sex- and age-matched healthy controls (n = 15). Moreover, when the patients with WG were classified as having active disease (n = 9) or being in remission (n = 9), we found that those with active disease had markedly raised CX3CL1 levels compared with the other WG patients (Fig. 1B).


Figure 1
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  		FIG. 1. (A) shows plasma levels of CX3CL1 in 18 patients with WG and 18 healthy controls. Horizontal lines represent median values. (B) shows WG patients classified as having active disease (n = 9) or being in remission (n = 9) according to the Birmingham Vasculitis Activity Score as well as levels of CRP and ESR (Table 1). Data are given as mean ± s.e.m. * P < 0.05 vs patients in remission.

 
CX3CR1 expression in PBMC in WG patients and healthy controls
As depicted in Fig. 2A, the raised plasma levels of CX3CL1 in WG were accompanied by a marked increase in mRNA levels of its corresponding receptor, CX3CR1, in PBMCs from these patients (n = 18) [~4-fold increase comparing controls (n = 15)]. Again, particularly high levels were found in those with active disease as compared with those in remission (P < 0.01). Flow cytometry data were available from eight of these WG patients and eight of the controls, showing that the increased CX3CR1 expression in PBMCs from WG patients mainly reflected an increased proportion of CX3CR1+CD3+CD4+ T cells, with no significant changes in the proportion of CD8+ T cells and monocytes expressing this chemokine receptor (Figs 2B–D and 3).


Figure 2
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  		FIG. 2. (A) shows gene expression of CX3CR1 in PBMC from 18 patients with WG and 15 healthy controls, normalized to the gene expression of the control gene GAPDH. (B–D) show surface expression of CX3CR1 as measured by flow cytometry in PBMCs from eight patients with WG and eight healthy controls. Data are presented as the percentage of the total amount of CD4+ T cells (B), CD8+ T cells (C) and CD14+ monocytes (D) (mean ± S.E.M). *P < 0.05 and **P < 0.001 vs healthy controls.

 

Figure 3
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  		FIG. 3. FACS analysis of CX3CR1 expression in T-cell subsets. The upper panels show CX3CR1 expression on CD4+ T cells in one representative WG patient and one representative healthy control presented as dot blots [control in (A) and WG patient in (B)] and histograms [control in (C) and WG patient in (D)]. The lower panels show CX3CR1 expression on CD8+ T cells in one representative WG patient and one representative healthy control presented as dot blots [control in (E) and WG patient in (F)] and histograms [control in (G) and WG patient in (H)].

 
CX3CR1-mediated chemotaxis, adhesion and MCP-1 response in PBMCs from WG patients and healthy controls
To elucidate any functional implications of the enhanced CX3CR1 expression in WG patients, we examined the chemotactic properties of PBMCs, T cells and monocytes, the adhesive properties of PBMCs, as well as the release of MCP-1, in response to CX3CL1 stimulation in eight of the WG patients with active disease and in eight of the controls. While CX3CL1 (chemokine domain) induced chemotaxis in a dose-dependent manner in cells from both WG patients and controls (data not shown), the response was significantly higher in PBMCs and T cells, but not in monocytes, from WG patients as compared with healthy controls (Fig. 4A–C). Moreover, also the CX3CL1 (full length) mediated cell adhesion was up-regulated in WG patients (Fig. 4D). The CC-chemokine MCP-1 has previously been implicated in the pathogenesis of WG [9, 10], and we therefore finally examined the efficacy of CXCL1 (chemokine domain, 100 ng/ml), to stimulate the secretion of this chemokine in PBMCs. As shown in Fig. 5, the MCP-1 secretion was significantly higher in PBMCs from WG patients with active disease as compared with controls, and this elevation was further increased by CX3CL1. In fact, no CX3CL1-mediated MCP-1 increase was seen in PBMCs from healthy controls, further underscoring that the increased expression of CX3CR1 in PBMCs from WG patients affects their functional potential.


Figure 4
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  		FIG. 4. Chemotaxis in response to soluble CX3CL1 (chemokine domain, 10 nM) of PBMCs (A), CD3+ T cells (B) and CD14+ monocytes (C) collected from eight WG patients with active disease and eight healthy controls (n = 8). (D) shows adhesion of PBMC in response to immobilized CX3CL1 (full length) in eight WG patients with active disease and eight healthy controls. The number of migrated and adherent cells was determined by counting the cells in five random higher power (400x) fields, and expressed as the mean number of cells per field. Data are mean ± S.E.M. *P < 0.05 and **P < 0.01 vs healthy controls.

 

Figure 5
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  		FIG. 5. MCP-1 levels in supernatants from unstimulated (unstim) and CX3CL1-stimulated (chemokine domain, 50 nM) PBMC in eight WG patients with active disease and eight healthy controls. PBMCs were cultured for 20 h and MCP-1 levels were analysed by enzyme immunoassay. Data are mean ± S.E.M. *P < 0.05 and **P < 0.01 vs corresponding levels in healthy controls. #P < 0.05 vs unstimulated cells.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
In the present study, we show that WG patients are characterized by markedly increased plasma levels of CX3CL1, accompanied by enhanced expression of its corresponding receptor, CX3XR1, in PBMC, with particularly high levels of both ligand and receptor in those with active disease. Although we do not have any data on the absolute numbers of the various cell subsets in peripheral blood, flow cytometry analyses suggest that the increased expression of CXC3CR1 in PBMC in WG patients primarily reflects an increased proportion of CX3CR1+CD3+CD4+ T cells. Importantly, the up-regulation of CX3CR1 in PBMC from WG patients affected their functional potential as shown by enhanced chemotactic, adhesive and other inflammatory responses (i.e. increased MCP-1 secretion) to CX3CL1 stimulation. Based on the ability of this chemokine to promote leucocyte infiltration into the vessel wall, it is tempting to hypothesize that increased CX3CL1/CX3CR1 interaction could be involved in the pathogenesis of the granulomatous vasculitis characterizing WG.

Chemokines play an important part in attracting and activating of leucocytes in inflamed tissue, and these properties make them attractive candidate mediators in the pathogenesis of WG. Previously, enhanced expression of RANTES, macrophage inflammatory peptide (MIP)-1Formula and MIP-1Formula has been found in WG lung lesions [6, 11], and there are also some reports of increased chemokine expression in renal biopsies from WG patients [25, 26]. Moreover, proteinase-3 has been shown to enhance IL-8 production in endothelial cells and monocytes [7, 8], and we have recently reported raised plasma levels of MCP-1 and IL-8 in WG [9]. Previously, increased CX3CL1 expression has been found in various autoimmune and vasculitic disorders such as SLE and rheumatoid arthritis, potentially contributing to neuropsychiatric manifestations and synovitis, respectively [15, 17]. Moreover, studies in animal models have shown that CX3CL1 inhibition may delay the initiation and progression of lupus nephritis [27]. Cockwell et al. [28] have previously reported increased mRNA levels of CX3CL1 in renal biopsies from patients with cANCA-positive vasculitic glomerulonephritis, and in the present study we extend these findings by showing increased levels of CX3CL1/CX3CR1 in peripheral blood from WG patients. It is tempting to hypothesize that CX3CL1/CX3CR1 interaction may be involved in the pathogenesis of this type of vasculitis.

The expression of CX3CL1 on the endothelium is generally low in healthy individuals in the absence of an inflammatory insult, but the expression of both the membrane-bound and the secreted form is greatly induced by inflammatory cytokines [13]. The markedly elevated plasma levels of CX3CL1 in WG-patients could therefore potentially reflect persistent endothelial cell-related inflammation in the WG lesions. Moreover, the increased expression of CX3CR1 in PBMCs, as shown by both quantitative and functional assays, could through interaction with CX3CL1 further facilitate migration of leucocyte subsets into the WG lesions. In fact, since the increased levels of CX3CL1 in plasma may be derived from inflamed endothelium in WG lesions, concentrations of these molecules would be expected to be higher in lesions than in plasma, potentially establishing a chemotactic gradient mediating leucocyte migration into inflamed tissues. Furthermore, while CX3CL1 had no effect on MCP-1 secretion in PBMCs from healthy controls, it significantly increased MCP-1 release in PBMCs from WG patients. Such a CX3CL1-mediated MCP-1 release could well occur in the vascular lesions of WG, where it could further promote vascular inflammation. Interestingly, MCP-1 has been reported to increase CX3CR1 expression in mononuclear cells [29], and it is tempting to hypothesize that the inflammatory interaction between MCP-1 and CX3CL1/CX3CR1, involving endothelial cells and leucocytes, could contribute to vascular inflammation in WG, representing an inflammatory loop in this disorder.

WG is characterized by expansion of T helper 1 (Th1)-type cells. Thus, raised levels of Th1-related cytokines such as interferon (IFN){gamma} and IL-12 have been reported in these patients [30], and a Th1 cytokine pattern has also been found to predominate in the granulomatous inflammation in WG patients [31]. In the present study, we report an increased proportion of CX3CR1+CD3+CD4+ T cells in WG patients. Previous studies have shown that CX3CR1+ CD3+T cells are terminally differentiated effector phenotypes with enhanced cytotoxic properties [32], and interestingly enough, recent studies suggest that CX3XR1 is preferentially expressed on Th1 cells compared with Th2 cells [33]. Fraticelli et al. [33] reported increased endothelial expression of CX3CL1 in Th1-dominated disorders (e.g. psoriasis and Mycobacterium tuberculosis granulomatous lymphadenitis), but not in Th2-driven disorders (e.g. atopic dermatitis). Our findings in the present study may therefore further support the involvement of T cell activation, and in particular Th1-driven responses, in WG, possibly leading to vascular inflammation and tissue damage.

The use of immunosuppressive medications in WG patients, with the most aggressive treatment modalities in those with active disease, could clearly influence the levels of various inflammatory mediators. However, although some of these medications could cause endothelial damage and thereby potentially enhanced release of CX3CL1, the use of these drugs are more likely to down-regulate CX3CL1/CX3CR expression. Thus, we have recently shown that cortiocosteroids decrease chemokine expression in PBMCs in WG patients [9], and these medications have also been shown to attenuate CX3CL1 expression in the kidneys of patients with human crescentic glomerulonephritis [34]. Nevertheless, the ability of the various treatment modalities to modulate CX3CL1/CX3CR1 expression in different tissues will have to be examined in forthcoming studies.

In the present study, we reported increased systemic expression of CX3CL1 and its corresponding receptor, CX3CR1, on T cells in WG, potentially contributing to vascular inflammation in this disorder. Future studies will clarify if strategies to target CX3CL1/CX3CR1 interaction could provide a new therapeutic approach in WG, potentially blocking endothelial cell inflammation, leucocyte infiltration and Th1-mediated responses.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by grants from the Research Council of Norway and the University of Oslo.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 6 March 2007; revised version accepted 18 May 2007.
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