Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and TH1-like/CD45RO+T cells

Weber, Christian; Weber, Kim S.C.; Klier, Christiane; Gu, Songhai; Wank, Rudolf; Horuk, Richard; Nelson, Peter J.

doi:10.1182/blood.v97.4.1144

Cited by 237 publications

(200 citation statements)

References 24 publications

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“…In contrast, our data clearly demonstrate the nonredundant role of CCR1 (ligands CCL3 and CCL4) for renal leukocyte recruitment after UUO in mice. The finding that CCR1 is important for renal leukocyte recruitment in vivo is consistent with in vitro data showing that CCR1 but not CCR5 is essential for the initial leukocyte attachment to endothelium (14). Initial attachment mediated by CCR1 is therefore critical for renal leukocyte recruitment.…”

Section: Lack Of Ccr5 Expression Does Not Affect Leukocyte Infiltratisupporting

confidence: 79%

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Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Eis¹,

Luckow²,

Vielhauer³

et al. 2004

Journal of the American Society of Nephrology

121

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Abstract. As chemokine receptor CCR1 and CCR5 expression on circulating leukocytes is thought to contribute to leukocyte recruitment during renal fibrosis, the authors examined the effects of unilateral ureteral obstruction (UUO) in mice deficient for CCR1 or CCR5. Analysis of UUO kidneys from CCR1-deficient mice revealed a reduction of interstitial macrophages and lymphocytes (35% and 55%, respectively) compared with wild-type controls. CCR1-deficient mice had reduced CCR5 mRNA levels in UUO kidneys, which correlated with a reduction of CCR5ϩ T cell infiltrate as determined by flow cytometry. Interstitial fibroblasts, renal TGF-␤1 mRNA expression, interstitial volume, and collagen I deposits were all significantly reduced in CCR1-deficient mice. In contrast, renal leukocytes and fibrosis were unaffected in CCR5-deficient mice with UUO. However, if treated with the CCR1 antagonist BX471, CCR5-deficient mice showed a similar reduction of renal leukocytes and fibrosis as CCR1-deficient mice. To determine the underlying mechanism labeled macrophages and T cells isolated from either wild-type, CCR1-deficient, or CCR5-deficient mice were injected into wild-type mice with UUO.

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Section: Lack Of Ccr5 Expression Does Not Affect Leukocyte Infiltratisupporting

confidence: 79%

“…In vitro studies have suggested different roles of CCR1 and CCR5 for leukocyte recruitment. CCR1 but not CCR5 was found to be required for the initial adhesion of human monocytes and T cells to activated endothelium, whereas CCR5 seemed to be involved in the subsequent transendothelial cell migration (14).…”

mentioning

confidence: 99%

Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Eis¹,

Luckow²,

Vielhauer³

et al. 2004

Journal of the American Society of Nephrology

121

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“…We have previously demonstrated that CCR5 can mediate unique signaling events (14,15). In addition, we have shown that human Hsp70 from melanoma cells can chaperone tumor-associated peptides (tyrosinase) and deliver them to DCs allowing cross-presentation and T cell stimulation (16).…”

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confidence: 99%

Calcium Signaling in Dendritic Cells by Human or Mycobacterial Hsp70 Is Caused by Contamination and Is Not Required for Hsp70-mediated Enhancement of Cross-presentation

Bendz

Marincek

Momburg

et al. 2008

Journal of Biological Chemistry

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Extracellular heat shock proteins (HSPs) can stimulate antigen-specific immune responses. Using recombinant human (rhu)Hsp70, we previously demonstrated that through complex formation with exogenous antigenic peptides, rhuHsp70 can enhance cross-presentation by antigen-presenting cells (APCs) resulting in stronger T cell stimulation. T cell stimulatory activity has also been described for mycobacterial (myc)Hsp70. MycHsp70-assisted T cell activation has been reported to act through the binding of mycHsp70 to chemokine receptor 5 (CCR5), calcium signaling, phenotypic maturation, and cytokine secretion by dendritic cells (DCs). We report that highly purified rhuHsp70 and mycHsp70 proteins both strongly enhance cross-presentation of exogenous antigens. Augmentation of cross-presentation was seen for different APCs, irrespective of CCR5 expression. Moreover, neither of the purified Hsp70 proteins induced calcium signals in APCs. Instead, calcium signaling activity was found to be caused by contaminating nucleotides present in Hsp70 protein preparations. These results refute the hypothesis that mycHsp70 proteins require CCR5 expression and calcium signaling by APCs for enhanced antigen cross-presentation for T cell stimulation.Recent evidence has demonstrated that heat shock proteins (HSPs), 2 in addition to their roles as chaperones, can stimulate antigen-specific immune responses (1). This immune stimulatory activity is thought to be activated after HSPs are released from cells either through necrosis or induced secretion (2-5).In their role as molecular chaperones, most HSPs exist in complexes with hydrophobic polypeptides. The contact of extracellular HSP:peptide complexes with dendritic cells (DCs) is thought to result in the efficient transfer of the chaperoned peptides into the antigen-presentation pathway of DCs allowing antigen-specific T cell activation.Mechanistically, HSP binding to surface receptors and HSP-induced signaling events are thought to be involved in antigen transfer to DCs and subsequent T cell stimulation. In this regard, a number of potential HSP receptors have been reported (6 -9). Among these, CD40 and chemokine receptor 5 (CCR5) represent two interesting possibilities as these molecules are intricately linked to T cell and DC biology (10, 11). In this regard, CCR5 has been reported to act as a pattern recognition receptor for mycobacterial (myc)Hsp70 thus facilitating mycobacterial defense through mycHsp70-induced DC activation and subsequent T cell stimulation. The binding of mycHsp70 to CCR5, calcium signaling in myeloid DCs, phenotypic maturation, and cytokine secretion of DCs have been reported to underlie mycHsp70-assisted T cell activation (12, 13).We have previously demonstrated that CCR5 can mediate unique signaling events (14, 15). In addition, we have shown that human Hsp70 from melanoma cells can chaperone tumor-associated peptides (tyrosinase) and deliver them to DCs allowing cross-presentation and T cell stimulation (16). Recently, we used recombinant human (rhu)Hsp70 to def...

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“…6,7 CCR1 and CCR5 are expressed on various cell types implicated in atherosclerosis, eg, monocytes/macrophages, T lymphocytes, or Th1-type cells, and are special-ized in mediating RANTES-triggered arrest and transendothelial diapedesis of these cells. [7][8][9] Further to ligand binding and leukocyte attraction, these receptors can induce activation and detrimental effects of emigrated cells at the lesion sites. 10 RANTES is detectable in atherosclerotic plaques and deposited on early atherosclerotic endothelium by activated platelets, where it triggers arrest of circulating monocytes.…”

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confidence: 99%

Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice

Braunersreuther

Zernecke

Arnaud

et al. 2007

ATVB

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251

189

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Objective-Chemokines and their receptors are crucially involved in the development of atherosclerotic lesions by directing monocyte and T cell recruitment. The CC-chemokine receptors 1 (CCR1) and 5 (CCR5) expressed on these cells bind chemokines implicated in atherosclerosis, namely CCL5/RANTES. Although general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 have not been unequivocally determined. Methods and Results-We provide two independent lines of investigation to dissect the effects of Ccr1 and Ccr5 deletion in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice in a collaboration between Aachen/Germany and Geneva/Switzerland. Different strains of ApoE Ϫ/Ϫ Ccr5 Ϫ/Ϫ mice, ApoE Ϫ/Ϫ Ccr1 Ϫ/Ϫ mice or respective littermates, were fed a high-fat diet for 10 to 12 weeks. Plaque areas were quantified in the aortic roots and thoracoabdominal aortas. Concordantly, both laboratories found that lesion formation was reduced in ApoE Ϫ/Ϫ Ccr5 Ϫ/Ϫ mice. Plaque quality and immune cells were assessed by immunohistochemistry or mRNA analysis. Whereas lesional macrophage content, aortic CD4, and Th1-related Tim3 expression were reduced, smooth muscle cell (SMC) content and expression of interleukin-10 in plaques, lesional SMCs, and splenocytes were elevated. Protection against lesion formation by Ccr5 deficiency was sustained over 22 weeks of high-fat diet or over 26 weeks of chow diet. Conversely, plaque area, T cell, and interferon-␥ content were increased in ApoE Ϫ/Ϫ Ccr1 Ϫ/Ϫ mice. Conclusion-Genetic deletion of Ccr5 but not Ccr1 in ApoEϪ/Ϫ mice protects from diet-induced atherosclerosis, associated with a more stable plaque phenotype, reduced mononuclear cell infiltration, Th1-type immune responses, and increased interleukin-10 expression. This corroborates CCR5 as a promising therapeutic target. (Arterioscler Thromb Vasc Biol.

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Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and TH1-like/CD45RO+T cells

Cited by 237 publications

References 24 publications

Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Calcium Signaling in Dendritic Cells by Human or Mycobacterial Hsp70 Is Caused by Contamination and Is Not Required for Hsp70-mediated Enhancement of Cross-presentation

Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice

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