Dual Role of CCR2 during Initiation and Progression of Collagen-Induced Arthritis: Evidence for Regulatory Activity of CCR2+ T Cells

Brühl, Hilke; Cihak, Josef; Schneider, Martin; Plachý, Jiřı́; Rupp, Tamara; Wenzel, Isabell; Shakarami, Mehdi; Milz, Stefan; Ellwart, Joachim W.; Stangassinger, M.; Schlöndorff, Detlef; Mack, Matthias

doi:10.4049/jimmunol.172.2.890

Cited by 168 publications

(150 citation statements)

References 37 publications

(39 reference statements)

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“…Results of staining for CCR2 on monocytes and basophils are representative of at least 3 experiments. majority of CD4ϩ,CCR2ϩ T cells also stain positive for the regulatory T cell markers CD25 and CD103 and fulfill functional criteria of regulatory T cells in vitro (13).…”

Section: Resultsmentioning

confidence: 83%

“…We have previously shown that treatment with a blocking mono-clonal antibody (mAb) against CCR2, MC-21, administered at 500 g every third day, improves arthritis, when the treatment is started before the first immunization with collagen (13). In contrast, when the treatment is started later, a marked aggravation of arthritis occurs.…”

mentioning

confidence: 99%

“…We have previously reported that CCR2 is expressed on murine regulatory T cells, which may be compromised by treatment with MC-21 (13). In addition, we noted that DBA/1 mice treated with MC-21 during disease progression had massively elevated levels of interleukin-6 (IL-6) in their plasma (Brühl H, et al: unpublished observations).…”

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confidence: 99%

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

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

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106

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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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Section: Resultsmentioning

confidence: 83%

mentioning

confidence: 99%

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

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

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106

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“…The severity of arthritis was evaluated using the following 2 parameters: synovial inflammation (0 ϭ normal, 1 ϭ focal inflammatory infiltrates, and 2 ϭ inflammatory infiltrate that dominates the cellular histology) and bone destruction (0 ϭ normal, 1 ϭ small areas of bone destruction, 2 ϭ widespread bone destruction), as described previously (32,33). Statistical analysis.…”

Section: Nanki Et Almentioning

confidence: 99%

Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis

Nanki¹,

Shimaoka²,

Hayashida³

et al. 2005

Arthritis & Rheumatism

135

114

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Objective. Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive T cell infiltration into the synovium. The accumulated T cells express type 1 cytokines, such as interferon-␥ (IFN␥) and tumor necrosis factor ␣, and activated markers of inflammation, such as CD154 and inducible costimulator (ICOS). It is thought that chemokines contribute to T cell accumulation in the synovium. In this study, we examined the role of CXCL16 and CXCR6 in T cell migration and stimulation in RA synovium.Methods. Expression of CXCL16 and CXCR6 was analyzed by immunohistochemistry, reverse transcription-polymerase chain reaction, Western blotting, and/or flow cytometry. Migration activity was assessed using a chemotaxis chamber. IFN␥ production was analyzed by enzyme-linked immunosorbent assay. The effect of anti-CXCL16 monoclonal antibody on murine collagen-induced arthritis (CIA) was evaluated.Results. CXCL16 was expressed in RA synovium.

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“…In addition to the effects of the CCR2 null mutation in infection models, CCR2-deficient mice failed to recruit macrophages in a model of sterile peritoneal inflammation induced by thioglycollate [27][28][29][30][31]. Antibody blockade of CCR2 also prevented macrophage accumulation in thioglycollate peritonitis [32], but did not inhibit infiltration of inflamed joints by monocytes during progression of collagen-induced arthritis suggesting that under certain conditions of inflammation recruitment of macrophages may be independent of CCR2 [33].…”

Section: Introductionmentioning

confidence: 99%

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

Feterowski

Mack²,

Weighardt

et al. 2004

Eur J Immunol

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Chemokine receptors are important for recruiting leukocytes to sites of infection and may contribute to immune cell activation. The present study investigated the role of the chemokine receptor CCR2 in polymicrobial septic peritonitis. The results showed that peritoneal production of the CCR2 ligands CCL2 and CCL12 in septic mice was largely independent of the common Toll-like receptor signaling adaptor MyD88. Antibody blockade of CCR2 reduced the recruitment of macrophages and neutrophils to the infected peritoneal cavities of both wild-type and MyD88-deficient mice, suggesting that CCR2 engagement contributes to the MyD88-independent cellular response against polymicrobial septic peritonitis. Notably, administration of blocking CCR2 antibodies markedly increased local and systemic IL-10 levels in septic wild-type mice, whereas IL-10 was not detected in MyD88-deficient mice irrespective of whether CCR2 was blocked or not. Inhibition of CCR2 directly augmented Tolllike receptor-induced IL-10, but not TNF and IL-6, production of macrophages in vitro. Concomitant with enhanced IL-10 production, CCR2 blockade caused impaired bacterial clearance and aggravated kidney injury in wild-type, but not MyD88-null mice. These results indicate that CCR2 engagement modulates the innate immune response to polymicrobial septic peritonitis by both MyD88-dependent and -independent processes and suggest that a major function of CCR2 in sepsis is to attenuate IL-10 production and IL-10-mediated suppression of host defense.

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Dual Role of CCR2 during Initiation and Progression of Collagen-Induced Arthritis: Evidence for Regulatory Activity of CCR2+ T Cells

Cited by 168 publications

References 37 publications

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

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

Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

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