Defects in Macrophage Recruitment and Host Defense in Mice Lacking the CCR2 Chemokine Receptor

Kurihara, Takao; Warr, Glenn A.; Loy, James; Bravo, Rodrigo

doi:10.1084/jem.186.10.1757

Cited by 629 publications

(481 citation statements)

References 34 publications

Supporting

Mentioning

442

Contrasting

Unclassified

Order By: Relevance

“…The chemokine receptors CCR2 and CXCR2 are required for monocytes and neutrophils, respectively, to egress from the bone marrow into the blood during steady state and infection [7][8][9][10]. They are also central for monocyte and neutrophil recruitment and host survival during infections [9,[11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…39: 3019-3030 DOI 10.1002 Immunity to infection 3019 marrow into the blood during steady state and infection [7][8][9][10]. They are also central for monocyte and neutrophil recruitment and host survival during infections [9,[11][12][13][14][15][16]. Despite the undisputed role of chemokine receptors and their ligands in ensuring survival to infection, it is difficult to assess the role of individual chemokines in phagocyte recruitment, particularly in the complex environment of bacterial-infected tissues.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

Rydström

Wick

2009

Eur J Immunol

View full text Add to dashboard Cite

Oral Salmonella infection recruits phagocytes to Peyer's patches (PP) and MLN. The chemokines induced in infected PP and MLN, the cellular sources during infection and the TLR signaling pathways involved in vivo are not known. Here, we show that CCL2, CXCL9 and CXCL2 mRNA are up-regulated in PP and MLN coincident with the first arrival of monocytes and neutrophils. Laser capture microdissection microscopy revealed that chemokine mRNA up-regulation was differently distributed in PP. Despite this, recruited monocytes and neutrophils formed inflammatory cell clusters throughout PP. Monocytes and neutrophils purified from infected mice preferentially produced CXCL2 and small amounts of CCL2, and neutrophils from infected mice migrated towards CXCL2 and CCL3. Furthermore, phagocyte recruitment to PP and MLN was intact in mice lacking TLR4 alone and when signaling through TLR4 and TLR5 was simultaneously absent; however, recruitment was compromised in MyD88 À/À and more so in MyD88 À/À TLR4 À/À double knockout mice. Phagocyte release into the blood, however, was only marginally reduced in MyD88 À/À TLR4 À/À mice. Defective phagocyte recruitment to PP and MLN of MyD88 À/À TLR4 À/À mice was paralleled by low chemokine induction. These data provide insight into the chemokines and TLR signaling pathways that orchestrate the early phagocyte response to oral Salmonella infection.Key words: Chemokine . Monocyte . Salmonella . TLR IntroductionMonocytes and neutrophils are critical in the first line of defense against bacteria. They develop in the bone marrow, are released into the circulation and enter tissues in response to infection. Murine monocytes in the blood are a heterogeneous population and have been divided into two main subsets based on whether they are present in steady state or recruited under inflammatory conditions [1]. Inflammatory Gr-1 hi CCR2 hi CX 3 CR1 low monocytes, which have also been called TipDC upon entering a tissue, are a source of molecules important in controlling bacterial infection, particularly iNOS and TNF-a [2][3][4].Salmonella enterica serovar Typhimurium (S. typhimurium) is a Gram-negative facultative intracellular bacterium that infects via the oral route. Orally acquired Salmonella exits the gut lumen primarily by crossing the follicle-associated epithelium overlying Peyer's patches (PP) via M cells (reviewed in [5]). The bacteria are then further spread to the MLN, most likely by DC, and to the spleen and liver via the blood [5,6]. After oral infection with S. typhimurium, neutrophils and Gr-1 hi CCR2 hi inflammatory monocytes accumulate in PP and MLN, the first organs encountering the bacteria, beginning 2-3 days after infection [3].Chemokines are the main mediators involved in the recruitment and migration of leukocytes to and within tissues. An array of chemokines is induced by inflammation and recruits monocytes, neutrophils and other cells to sites of infection. The chemokine receptors CCR2 and CXCR2 are required for monocytes and neutrophils, respectively, to egress from the bone ...

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

Rydström

Wick

2009

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…Thus, genetic ablation of CCR2 caused an increased susceptibility to Listeria monocytogenes, Leishmania major and Cryptococcus neoformans infections and was associated with an impaired production of IFN-c and/or an increase in IL-4 and IL-5. 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

View full text Add to dashboard Cite

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.

show abstract

“…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)(10)(11)(12).…”

mentioning

confidence: 99%

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

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

108

View full text Add to dashboard Cite

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,

show abstract

Defects in Macrophage Recruitment and Host Defense in Mice Lacking the CCR2 Chemokine Receptor

Cited by 629 publications

References 34 publications

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

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

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

Contact Info

Product

Resources

About