This study investigated the expression of a broad variety of chemokines and chemokine receptors in paired samples of ST and PB from patients with RA, inflammatory OA, and ReA. Of interest, the percentages of CCR1 and CCR5 positive monocytes were decreased in PB of patients with RA compared with normal subjects. There was abundant expression of CCR1 and CCR5 in the ST of these patients, indicating up regulation of these receptors and/or accumulation of CCR1 and CCR5 positive cells in the inflamed synovium.
Chemokines and chemokine receptors are important mediators of leucocyte trafficking in inflammatory disorders and many family members may be potential targets for biological intervention in a variety of diseases.17
As many of the chemokines and receptors have a role in cell migration and inflammation, it is difficult to predict which ligands or receptors are the best candidates to target. Studying their expression in paired ST and PB of the same patients will assist in the process of selecting the best candidates for therapeutic intervention.
Both CCR1 and CCR5 have been shown to have a specialised role in the recruitment of monocytes and Th1‐type T cells under inflammatory conditions.18
In RA, CCR1 and CCR5 have been implicated as potential therapeutic targets as they seem strongly involved in monocyte and T lymphocyte recruitment towards the joints.19
Although both cell types are intimately involved in the pathogenesis of RA, it was recently shown that ST macrophages, in particular, are related to clinical signs and symptoms.20,21,22,23
Both CCR1 and CCR5 have been shown to be expressed on a large number of ST macrophages. Interference with the migration of these cells by cytokine receptor blockade is therefore suggested as a new therapeutic approach to reduce synovial inflammation. The only published study on chemokine blockade in patients so far indicated that short term treatment with a specific CCR1 antagonist resulted in an evident reduction in the number of ST macrophages.8
The results of our study confirm the expression of both CCR1 and CCR5 in the ST and PB of patients with RA and other arthritides, but also show that other chemokine receptors and chemokines are involved as well. Although these data do not prove that these chemokine receptors have a functional role in arthritis, it can be expected that they are involved in the inflammatory process based on reported functional studies.18
Except for CCL5/RANTES and CCL15/HCC‐2, which were present at higher levels in RA ST, there were on average no significant differences in the expression of the analysed chemokine receptors and chemokines in RA compared with the disease controls, indicating that chemokines and chemokine receptors are not uniquely restricted to inflammation in RA. Thus based on these expression data, chemokine blockade might not only be a potential treatment for patients with RA but also for other inflammatory joint disorders, because this approach is directed at common final pathways.
In addition to chemokine receptors, we investigated the expression of many of their ligands in the synovium. Our results confirm earlier reports that there is abundant expression of CCL2/MCP‐1, mainly in the intimal lining layer, and CCL5/RANTES, diffusely expressed in ST, especially in patients with RA.24,25
CCL7/MCP‐3 and CCL8/MCP‐2, which are ligands of both CCR1 and CCR2, were expressed abundantly in the ST both of patients with RA and disease controls. These ligands are structurally similar to CCL2/MCP‐1 and influence migration of especially lymphocytes and monocytes.26
This is the first description of CCL7/MCP‐3 and CCL8/MCP‐2 in ST. The expression of CCL7/MCP‐3 and CCL8/MCP‐2 resembles that of CCL2/MCP‐1, with marked expression by FLS and macrophages in the intimal lining layer.
In addition, this study shows for the first time the expression of CCL14/HCC‐1, CCL15/HCC‐2, and CCL16/HCC‐4, ligands of CCR1, in the inflamed synovium. CCL14/HCC‐1 differs from most chemokines as it is present in high concentrations in human plasma.27
CCL14/HCC‐1 is a low affinity agonist of CCR1, which is converted into a high affinity agonist of CCR1 (and CCR5) by serine proteases.28
CCL15/HCC‐2, which binds to CCR1 and CCR3, has a chemoattractant role for neutrophils, lymphocytes, and monocytes.29
Besides having chemotactic and proinflammatory effects, CCL15/HCC‐2 is also known to promote homoeostasis and was reported to be expressed only in the gut and the liver.30,31
CCL16/HCC‐4 is another chemokine expressed in the liver, which is also known to be up regulated in colonic biopsy samples from patients with ulcerative colitis.32
It has been suggested that this chemokine is an effective inducer of cell adhesion and it has been shown to activate angiogenic programmes in vascular endothelial cells.33,34
The results of our study show that these inflammatory mediators are present in the ST of all patient groups. CCL15/HCC‐2 was expressed at higher levels in the ST of patients with RA. Immunofluorescence double staining showed that more than half of the CD3+ T cells and CD68+ macrophages and more than 70% of the CD55+ FLS coexpressed CCL15/HCC‐2. This indicates that CCL15/HCC‐2 may be an important contributor to cell migration in synovitis.
Taken together, the data indicate that activation of the chemokine network represents a pivotal common final pathway in synovial inflammation. The strong expression of chemokine receptors in the ST may be explained by up regulation of the receptors or increased migration of cells expressing these receptors towards the site of inflammation, or a combination of both. The abundant expression of CCR1 and CCR5 in rheumatoid ST, in combination with their decreased expression on monocytes from paired PB, suggests a possible role in the migration of mononuclear cells from the PB towards the joints. Both monocytes and lymphocytes may participate in this process.
In addition, based on our data, CCR1 also appears to have a role in other joint diseases. Interference with this mechanism may result in decreased infiltration of leucocytes into the joints and a subsequent improvement in signs and symptoms, as recently was described for the effects of a specific CCR1 antagonist in patients with RA.8
Although other receptors and ligands are involved as well, blockade of CCR1 and CCR5 may be a potentially effective treatment for a variety of arthritides. This study provides the rationale for current and future functional studies and, subsequently, for clinical trials investigating the true potential of their application as therapeutic targets in patients.