Characterization of a chimeric chemokine as a specific ligand for ACKR3

Ameti, Rafet; Melgrati, Serena; Radice, Egle; Cameroni, Elisabetta; Hub, Elin; Thelen, Sylvia; Rot, Antal; Thelen, Marcus

doi:10.1002/jlb.2ma1217-509r

Cited by 22 publications

(36 citation statements)

References 62 publications

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“…mCCL20yAF 647 (15 µl, 30 nM in PBS) was injected into the food pad of wild‐type C57BL/6 mice, CCR6 ko C57BL/6 mice, 41 kindly provided by Sergio Lira, or heterozygous (ACKR4 GFP/wt ) and homozygous (ACKR4 GFP/GFP ) ACKR4‐EGFP knock‐in reporter mice 42 . After 15 min animals were sacrificed, the draining popliteal lymph node removed and fixed with formaldehyde by placing the specimens in 4% paraformaldehyde for 5 h. Vibratome sections were prepared as described 30 and stained with anti‐podoplanin‐PE (clone eBio8.1.1; eBioscience, San Diego, CA, United States) and anti‐B220‐biotin (clone RA3‐6B2; BD PharMingen, Allschwil, Switzerland)/streptavidin pacific blue (Thermo Fischer Scientific). Mice were treated in accordance with guidelines of the Swiss Federal Veterinary Office and experiments were approved by the Dipartimento della Sanità e Socialità.…”

Section: Methodsmentioning

confidence: 99%

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CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4

Matti

D’Uonnolo

Artinger

et al. 2020

Journal of Leukocyte Biology

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The chemokine CCL20 is broadly produced by endothelial cells in the liver, the lung, in lymph nodes and mucosal lymphoid tissues, and recruits CCR6 expressing leukocytes, particularly dendritic cells, mature B cells, and subpopulations of T cells. How CCL20 is systemically scavenged is currently unknown. Here, we identify that fluorescently labeled human and mouse CCL20 are efficiently taken-up by the atypical chemokine receptor ACKR4. CCL20 shares ACKR4 with the homeostatic chemokines CCL19, CCL21, and CCL25, although with a lower affinity. We demonstrate that all 4 human chemokines recruit -arrestin1 and -arrestin2 to human ACKR4. Similarly, mouse CCL19, CCL21, and CCL25 equally activate the human receptor. Interestingly, at the same chemokine concentration, mouse CCL20 did not recruit -arrestins to human ACKR4. Further cross-species analysis suggests that human ACKR4 preferentially takes-up human CCL20, whereas mouse ACKR4 similarly internalizes mouse and human CCL20. Furthermore, we engineered a fluorescently labeled chimeric chemokine consisting of the N-terminus of mouse CCL25 and the body of mouse CCL19, termed CCL25_19, which interacts with and is taken-up by human and mouse ACKR4. K E Y W O R D SACKR4, atypical chemokine receptor, CCL19, CCL20, CCL21, CCL25, chemokine scavenging, -arrestin

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Section: Methodsmentioning

confidence: 99%

“…Here, we identify that ACKR4 is a specific scavenger for CCL20. Moreover and in accordance with the chimeric chemokine CXCL11_12, 30 we engineered a (fluorescent) chimeric chemokine consisting of the N‐terminus of CCL25 and the body of CCL19, that interacts with and is taken‐up by ACKR4.…”

Section: Introductionmentioning

confidence: 99%

CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4

Matti

D’Uonnolo

Artinger

et al. 2020

Journal of Leukocyte Biology

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“…A chemokine-like chimera, named CXCL11_12, has been reported as a high-affinity ACKR3-selective ligand. The structure of the engineered chimera consists of the N-terminus of CXCL12 and the main body and C-terminus of CXCL11, and the study showed the internalization of CXCL11_12 by mouse ACKR3, making the chimera a useful tool to study ACKR3 (Puddinu et al, 2017;Ameti et al, 2018).…”

Section: Chemokine and Peptide Binding To Cxcr4 And Ackr3mentioning

confidence: 99%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

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The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the smallmolecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio-and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENTTo investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.

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“…In addition, FC313, a cyclic pentapeptide ligand for CXCR7, which is modified at the I-Pro position with a bulky hydrophobic side chain, exhibited an improved bioactivity toward CXCR7 ( Sekiguchi et al, 2018 ). Most recently, Ameti et al (2018) reported a chimeric chemokine, which selectively binds to CXCR7. This chimera is composed of the N-terminus of CXCL11 and the main body and C-terminus of CXCL12 and selectively interacts with CXCR7 with high affinity, while not interfering with binding of CXCL11 and CXCL12 to their cognate receptors ( Ameti et al, 2018 ).…”

Section: Pharmacological Ligands Of Cxcr7mentioning

confidence: 99%

“…Most recently, Ameti et al (2018) reported a chimeric chemokine, which selectively binds to CXCR7. This chimera is composed of the N-terminus of CXCL11 and the main body and C-terminus of CXCL12 and selectively interacts with CXCR7 with high affinity, while not interfering with binding of CXCL11 and CXCL12 to their cognate receptors ( Ameti et al, 2018 ). We believe that all these newly generated ligands will be valuable pharmacologic tools for the study of CXCR7.…”

Section: Pharmacological Ligands Of Cxcr7mentioning

confidence: 99%

CXCR7 Targeting and Its Major Disease Relevance

2018

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Chemokine receptors are the target of small peptide chemokines. They play various important roles in physiological and pathological processes. CXCR7, later renamed ACKR3, is a non-classical seven transmembrane-spanning receptor whose function as a signaling or non-signaling scavenger/decoy receptor is currently under debate. Even for cell signaling mechanisms, there has been inconsistency on whether CXCR7 couples to G-proteins or β-arrestins. Several reasons may contribute to this uncertainty or controversy. In one hand, it has been neglected that CXCR7 has more than five natural ligands and unfortunately, most of the prior research only studied SDF-1 (CXCL12) and/or I-TAC (CXCL11); on the other hand, there are mounting evidence supporting ligand and tissue bias for receptor signaling, but limited such information is available for CXCR7. In this review we focus on summarizing the endogenous and exogenous ligands of CXCR7, the main diseases related to CXCR7 and the biased signaling events happening on CXCR7. These three aspects of CXCR7 pharmacologic properties may explain why the contradicting opinions of whether CXCR7 is a signaling or non-signaling receptor exist. Further, potential new direction and perspective for the study of CXCR7 biology and pharmacology are highlighted.

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Characterization of a chimeric chemokine as a specific ligand for ACKR3

Cited by 22 publications

References 62 publications

CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4

CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4

Modulators of CXCR4 and CXCR7/ACKR3 Function

CXCR7 Targeting and Its Major Disease Relevance

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