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  • Review Article
  • Published:

Tuning inflammation and immunity by chemokine sequestration: decoys and more

Key Points

  • Chemokines are small, secreted proteins with leukocyte chemoattractant and cytokine-like activities that are mediated by a distinct subfamily of G-protein-coupled receptors (GPCRs). As described in this Review, humans and viruses have evolved numerous strategies to elude chemokine activities and divert leukocyte recruitment.

  • Seven-transmembrane domain receptors that have high sequence similarity to chemokine receptors that bind chemokines with high affinity but do not elicit migration or conventional signalling have been described. This subfamily of silent or decoy receptors includes the chemokine receptors Duffy antigen receptor for chemokines (DARC), D6 and CCX-CKR.

  • Chemokine decoy receptors recognize distinct and complementary sets of ligands and are strategically expressed by different cell types. In vitro and in vivo data indicate that they dampen local inflammation.

  • Viruses and parasites have evolved multiple strategies to elude chemoattractants, including the expression of soluble and seven-transmembrane domain decoy receptors.

Abstract

A set of chemokine receptors are structurally unable to elicit migration or conventional signalling responses after ligand engagement. These 'silent' (non-signalling) chemokine receptors regulate inflammatory and immune reactions in different ways, including by acting as decoys and scavengers. Chemokine decoy receptors recognize distinct and complementary sets of ligands and are strategically expressed in different cellular contexts. Importantly, viruses and parasites have evolved multiple strategies to elude chemokines, including the expression of decoy receptors. So, decoy receptors for chemokines represent a general strategy to tune, shape and temper innate and adaptive immunity.

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Figure 1: Structure–function properties of chemokines and their receptors.
Figure 2: Ligand specificity and tissue distribution of chemokine decoy receptors.
Figure 3: Decoy receptors and tuning of innate and adaptive immunity in peripheral tissues.

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Acknowledgements

We thank M. Necci for graphical assistance. This work was supported by the Italian Association for Cancer Research, the Italian Ministry of University and Research (FIRB, COFIN and CNR funding), the Italian Ministry of Health, Fondazione Cariplo (NOBEL project), the European Commission (NNOCHEM project and Mugen project), and the Istituto Superiore della Sanità (AIDS project).

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Correspondence to Alberto Mantovani.

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DATABASES

Entrez Genome

myxoma virus

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multiple sclerosis

rheumatoid arthritis

FURTHER INFORMATION

Cytokine Family cDNA Database (dbCFC)

Cytokine Receptor Database

HUGO Gene Nomenclature Committee

Humanitas Fondazione per la Ricerca

IUPHAR Receptor Database

RCSB Protein Data Bank

Glossary

G-protein-coupled receptor

(GPCR). A receptor that comprises seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G-proteins, which are a family of trimeric, intracellular signalling proteins with common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.

Decoy receptors

The classic definition of a receptor involves ligand recognition and signalling. Decoy receptors recognize ligands with high affinity and specificity but fail to elicit a response, thereby acting as a molecular trap for the ligand and in some cases as dominant negatives for key components of the signalling receptor complex.

Scavenger receptors

Scavenger receptors were originally defined in macrophages and endothelial cells as any of a structurally diverse group of receptors with an ability to bind polyanionic ligands such as oxidized low-density lipoprotein, as occurs in atherosclerotic plaques. Most scavenger receptors also bind either microbial ligands or apoptotic cells. In a broader, more general sense, scavenger receptors are transmembrane molecules that are devoted to mopping up ligands.

DRY motif

An amino-acid motif composed of aspartic acid (D), arginine (R) and tyrosine (Y). It is highly conserved among G-protein-coupled receptors and is thought to be essential for G-protein-mediated signalling.

Tetraspanins

The tetraspanin family contains proteins that span the membrane four times with two exoplasmic loops, and that can be found at the cell surface. Whereas some are highly restricted to specific tissues, others are widely distributed. Members of this family have been implicated in cell activation and proliferation, adhesion, motility, differentiation, and cancer.

Senescence

A nearly irreversible stage of permanent G1 cell-cycle arrest, which is linked to morphological changes (flattening of the cells), metabolic changes and changes in gene expression.

Orphan receptor

A receptor without a known ligand.

Molecular mimicry

The presence of viral proteins that have a primary amino-acid sequence and structure that is related to those of host proteins, indicating that viruses might have 'captured' genes from the host during evolution.

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Mantovani, A., Bonecchi, R. & Locati, M. Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol 6, 907–918 (2006). https://doi.org/10.1038/nri1964

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