The chemokine network. I. How the genomic organization of chemokines contains clues for deciphering their functional complexity

Abstract

Chemokines are a superfamily of small structurally related cytokines that have evolved to form a complex network of proteins that typically regulate leucocyte traffic but also carry very diverse sets of immune and non-immune functions. Two general features of cytokines, redundancy and promiscuity, are particularly prominent in chemokines. In part, these properties result from repeated processes of gene duplication and diversification, which has led to the present complex genomic map of chemokines, which contains cases of non-allelic isoforms, copy number polymorphisms and classical allelic variation. This genomic complexity is compounded with pre-translational and post-translational mechanisms resulting in a complex network of proteins whose essential functions are maintained, constituting a remarkable case of robustness reminiscent of crucial metabolic pathways. This reflects the adaptation of a system under strong evolutive pressure, supporting the concept that the chemokine system is essential for the coordination, regulation and fine-tuning of the type of immune response. In this first review, we analyse currently available data on the chemokine superfamily, focusing on its complex genomic organization. Genes encoding essential inflammatory chemokines are grouped into defined chromosomal locations as clusters and miniclusters that, from the genetic point of view, can be considered single entities given their overall functions (many ligands of a cluster bind to a few shared receptors). We will try to interpret this genomic organization of chemokines in relation to the main functions acquired by each individual member or by each cluster. In a second review, we shall focus on the relationship of chemokine variability and disease susceptibility.

Fig. 1

Map of genomic organization of human chemokines. CC chemokines in red, CXC chemokines in green, CX3C chemokine in yellow and C chemokines in blue. Distances between genes are expressed in Kb. Gene or cluster chromosomal location is expressed as a distance from the beginning of chromosome (in Mb). Receptors are shown above each ligand. The orientation of each gene is showed by an arrow.

Fig. 2

Relationship between genomic organization and function of chemokines. Main cell types (and essential actions) targeted by individual or chemokine cluster are shown. Functions of homeostatic chemokines are underlined and functions of homeostatic/inducible chemokines are in italics. CC chemokines in red, CXC chemokines in green, CX3C chemokine in yellow and C chemokines in blue. Antagonist functions are represented by ⊥.