Surface expression of CC- and CXC-chemokine receptors on leucocyte subsets in inflammatory joint diseases

Brühl, Hilke; Wagner, Klaus; Kellner, H; Schattenkirchner, M; Schlöndorff, Detlef; Mack, Matthias

doi:10.1046/j.1365-2249.2001.01679.x

Cited by 72 publications

(56 citation statements)

References 46 publications

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“…While some authors were unable to detect expression of CXCR4 [6,7], others have described binding of SDF-1 § , SDF-1 § -induced Ca 2+ flux and migration [8][9][10]. We have detected a clear expression of CXCR4 on neutrophils from the synovial fluid of patients with different inflammatory joint diseases, whereas CXCR4 was hardly detectable in the peripheral blood of patients or normal blood donors, suggesting that CXCR4 on neutrophils could be functionally relevant in the setting of inflammation [11]. Therefore we further investigated the regulation and function of CXCR4 on neutrophils.…”

Section: Introductioncontrasting

confidence: 51%

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Brühl¹,

Cohen²,

Linder³

et al. 2003

Eur J Immunol

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We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up-regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell-derived factor (SDF)-induced migration and up-regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly downregulated after stimulation with TNF- § and IFN-+ , resulting in significantly decreased SDFinduced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several-fold increased in cytokine-stimulated neutrophils, suggesting a post-translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF- § and IFN-+ . b he down-modulation of CXCR4 surface expression in response to TNF- § and IFN-+ was fully reversible after cytokine removal. Further, CXCR4 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits. Internalization of CXCR4 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation.

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Section: Introductioncontrasting

confidence: 51%

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Brühl¹,

Cohen²,

Linder³

et al. 2003

Eur J Immunol

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“…CCR1 was only found on a minority of PMNs in both the peripheral blood and SF, and there were no significant differences in CCR1 expression between these groups (21). Neither CCR2 nor CCR5 expression was observed on infiltrating PMNs in RA (21). Here we show that all PMNs in the SF of RA patients express CCRL2.…”

Section: Discussionmentioning

confidence: 52%

“…A previous study demonstrated that joint-infiltrating PMNs in RA downregulate CXCR1 and CXCR2 and up-regulate CXCR4 (21). CCR1 was only found on a minority of PMNs in both the peripheral blood and SF, and there were no significant differences in CCR1 expression between these groups (21). Neither CCR2 nor CCR5 expression was observed on infiltrating PMNs in RA (21).…”

Section: Discussionmentioning

confidence: 87%

“…It has been reported that circulating PMNs constitutively express CXC receptor 1 (CXCR1) and CXCR2 and that induction of CXCR4, CCR1, CCR2, CCR5, and CCR6 can occur under certain conditions (12), suggesting that PMNs are capable of responding to multiple ligands. A previous study demonstrated that joint-infiltrating PMNs in RA downregulate CXCR1 and CXCR2 and up-regulate CXCR4 (21). CCR1 was only found on a minority of PMNs in both the peripheral blood and SF, and there were no significant differences in CCR1 expression between these groups (21).…”

Section: Discussionmentioning

confidence: 94%

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Up‐regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis

Galligan¹,

Matsuyama²,

Matsukawa³

et al. 2004

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by a cellular influx and destruction of the joint architecture. Chemokines characteristically regulate leukocyte recruitment and activation. Chemokine (CC motif) receptor-like 2 (CCRL2) is an orphan receptor with homology to other CC chemokine receptors. We undertook this study to examine CCRL2 expression in RA, cytokine regulation of expression, and the source of a putative ligand in an attempt to determine the role of this receptor during inflammation.Methods. Expression of CCRL2 on joint-infiltrating leukocytes was examined by immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary neutrophils using Northern and Western blotting and reverse transcriptase-polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2 (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system, and their migration in response to fractions of synovial fluid (SF) from RA patients was examined using a 48-well chamber.Results. CCRL2 expression was observed on all infiltrating neutrophils and on some macrophages obtained from the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that CCRL2 messenger RNA (mRNA) was rapidly up-regulated following stimulation with lipopolysaccharide (1 g/ml) or tumor necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were expressed in cytokinestimulated neutrophils. Cells expressing either of these splice variants migrated in response to a fraction of RA SF.Conclusion. CCRL2 expression is up-regulated on synovial neutrophils of RA patients. Inflammatory products present in the SF activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of RA.

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“…Data on CCR2 expression in humans and results from studies of CCR2-deficient mice (2-4) support the blockade of CCR2 as an effective strategy in the treatment of multiple sclerosis and diabetes. In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5)(6)(7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8).…”

mentioning

confidence: 71%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

109

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Objective. The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen-induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proinflammatory effects, how these effects can be avoided, and whether CCR2؉ monocytes are useful targets in the treatment of arthritis.Methods. Arthritis was induced in DBA/1 mice by immunization with type II collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay.Results. Crosslinkage of CCR2 activated basophils to release interleukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1؉,CCR2؉ monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen-induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.Conclusion. These results show that depletion of CCR2؉ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dosedependent proinflammatory effects of CCR2 mAb are taken into account.CCR2, a chemokine (CC motif) receptor, is considered a promising target for disorders such as multiple sclerosis, type II diabetes, and rheumatoid arthritis, and Phase I and II clinical trials are currently in progress (1). Data on CCR2 expression in humans and results from studies of CCR2-deficient mice (2-4) support the blockade of CCR2 as an effective strategy in the treatment of multiple sclerosis and diabetes. In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5-7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8). Monocytes are thought to play a major role in joint destruction, and their recruitment to sites of inflammation is crucially dependent on CCR2, as shown in several murine disease models (9-12).However, thus far, data from murine models of collagen-induced arthritis do not support CCR2 as a target for treatment of rheumatoid arthritis. We have previously shown that treatment with a blocking monoDrs. Brühl, Luckow,

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Surface expression of CC- and CXC-chemokine receptors on leucocyte subsets in inflammatory joint diseases

Cited by 72 publications

References 46 publications

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Up‐regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

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