Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz, Laura; Villares, Ricardo; Rodrı́guez-Fernández, José Luis; Rodrı́guez-Frade, José Miguel; Mellado, Mario

doi:10.1002/jlb.2mr1217-503r

Cited by 25 publications

(18 citation statements)

References 119 publications

(224 reference statements)

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“…This is best exemplified by an earlier study using cells co-expressing CXCR4 and CCR5 in combination with selective receptor antagonists (AMD3100 and maraviroc, respectively) ( 52 ). Finally, similar to chemokines in solution, chemokine receptors themselves are known to form dynamic aggregates through lateral movements on cell surfaces, which are thought to modulate ligand selectivity and transmembrane signaling properties ( 53 ). Chemokine receptor-mediated synergism has been difficult to prove, not least because of the diversity of GPCRs present on immune cells.…”

Section: Discussionmentioning

confidence: 99%

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

et al. 2020

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Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or β-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca 2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.

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Section: Discussionmentioning

confidence: 99%

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

et al. 2020

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“…Accumulating evidence showed that Cxcl13 and Ccl2 are known to be involved in pathogenesis of neuropathic pain via different forms of neuron-glia interaction in the spinal cord [ 20 , 21 ]. The chemokines by binding to the G protein-coupled receptors play an essential role in pathological pain conditions triggered by either peripheral inflammation or nerve injury [ 23 , 24 ]. Our results demonstrated that chemokine genes showed the greatest upregulation, such as Cxcl13 (6.426 fold increase), suggesting that chemokines play a crucial role in the development of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Analyses of gene expression profiles in the rat dorsal horn of the spinal cord using RNA sequencing in chronic constriction injury rats

Shi

Wang

et al. 2018

J Neuroinflammation

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BackgroundNeuropathic pain is caused by damage to the nervous system, resulting in aberrant pain, which is associated with gene expression changes in the sensory pathway. However, the molecular mechanisms are not fully understood.MethodsWistar rats were employed for the establishment of the chronic constriction injury (CCI) models. Using the Illumina HiSeq 4000 platform, we examined differentially expressed genes (DEGs) in the rat dorsal horn by RNA sequencing (RNA-seq) between CCI and control groups. Then, enrichment analyses were performed for these DEGs using Gene Ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Hierarchical Cluster, and protein-protein interaction (PPI) network.ResultsA total of 63 DEGs were found significantly changed with 56 upregulated (e.g., Cxcl13, C1qc, Fcgr3a) and 7 downregulated (e.g., Dusp1) at 14 days after CCI. Quantitative reverse-transcribed PCR (qRT-PCR) verified changes in 13 randomly selected DEGs. GO and KEGG biological pathway analyses showed that the upregulated DEGs were mostly enriched in immune response-related biological processes, as well as 14 immune- and inflammation-related pathways. The downregulated DEGs were enriched in inactivation of mitogen-activated protein kinase (MAPK) activity. PPI network analysis showed that Cd68, C1qc, C1qa, Laptm5, and Fcgr3a were crucial nodes with high connectivity degrees. Most of these genes which have previously been linked to immune and inflammation-related pathways have not been reported in neuropathic pain (e.g., Laptm5, Fcgr3a).ConclusionsOur results revealed that immune and defense pathways may contribute to the generation of neuropathic pain after CCI. These mRNAs may represent new therapeutic targets for the treatment of neuropathic pain.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1316-0) contains supplementary material, which is available to authorized users.

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“…Indeed, Robertson et al, (9) highlighted specifically the challenges of 'deconvoluting physiologically relevant dimerization interfaces from those that simply mediate crystal contacts' and this question has recently been the subject of review (10). Chemokine receptors represent a family of GPCRs for which there is strong evidence of 'dimerization' (11). CXCR4 has been particularly well studied, because of its roles in cancer and viral infections, including its function as a co-receptor for strains of the HIV-1 virus (12,13,14).…”

Section: Introductionmentioning

confidence: 99%

Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

Ward

Pediani

Marsango

et al. 2021

Journal of Biological Chemistry

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CXCR4, a member of the family of chemokine-activated G protein-coupled receptors, is widely expressed in immune response cells. It is involved in both cancer development and progression as well as viral infection, notably by HIV-1. A variety of methods, including structural information, have suggested the receptor may exist as a dimer or oligomer. However, the mechanistic details surrounding receptor oligomerization and its potential dynamic regulation remain unclear. Using both biochemical and biophysical means we confirm that CXCR4 can exist as a mixture of monomers, dimers and higher-order oligomers in cell membranes and show that oligomeric structure becomes more complex as receptor expression levels increase. Mutations of CXCR4 residues located at a putative dimerization interface result in monomerization of the receptor. Additionally, binding of the CXCR4 antagonist IT1t— a small, drug-like isothiourea derivative — rapidly destabilizes the oligomeric structure, while AMD3100, another well-characterized CXCR4 antagonist, does not. Although a mutation that regulates constitutive activity of CXCR4 also results in monomerization of the receptor, binding of IT1t to this variant promotes receptor dimerization. These results provide novel insights into the basal organization of CXCR4 and how antagonist ligands of different chemotypes differentially regulate its oligomerization state.

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Remodeling our concept of chemokine receptor function: From monomers to oligomers

Cited by 25 publications

References 119 publications

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

Analyses of gene expression profiles in the rat dorsal horn of the spinal cord using RNA sequencing in chronic constriction injury rats

Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

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