For example, CCR5 expression has recently been shown to be pivotal in resistance to infection with the West Nile virus in humans [ 8 ]. The protective mechanism of CCR5 may involve directing leukocytes to the brain, where they can fight the infection more effectively [ 9 ]. Another hypothesis, however, involves 'viral' chemokines, believed to be mammalian genes that were at some point 'hijacked' by viruses.
To cope with the proliferation of such viral chemokines, mammals may have increased the numbers of their own endogenous chemokines to circumvent the effects of the viral molecules.
The chemokine system in acute inflammation
This higher affinity ligand would give an evolutionary advantage for an organism when coping with viral infections. These hypotheses also explain the lack of correspondence between cluster chemokine ligands in mouse and human, which may reflect the 'infectious experience' of the two species after they separated. This effect is shown graphically in the separation of the human and mouse chemokine clusters in the phylogenetic tree shown in Figure 2 : in the groups of chemokines there is often no one-to-one correspondence between human and mouse genes or the relationships between them may be uncertain.
This evolution is ongoing, and it is therefore possible that variations in these genes will be documented even among relatively close species.
The CCL1 gene is located in the MCP subregion Figure 3a but is rather distantly related to other members of the MCP group Figure 2a , suggesting that it was generated much earlier than the rest of the cluster chemokines in this region. In fact, CCL1 may represent an early chemokine that branched before the CC cluster chemokines in the phylogenetic tree Figure 2a. It is therefore possible that this chemokine-receptor pair has specific roles in shaping the immune system [ 16 ] and, in this context, its expression by T regulatory cells [ 13 ] is intriguing.
By contrast, the non-cluster or mini-cluster chemokines are relatively conserved between species and tend not to act on multiple receptors Table 1 , Figure 1. The evolutionary model described above predicts that these particular chemokine ligand-receptor pairs probably have pivotal roles in the development of the organism or in the function of physiological systems necessary for the organism's survival to reproductive age in other words, they are under evolutionary pressure.
In support of this hypothesis, the genes for most homeostatic chemokines are found in non-cluster chromosomal locations Table 1 , Figure 3b,c. For example, CXCR4-deficient and CXCLdeficient mice both have a lethal phenotype, and their embryos have various defects in critical organs, such as the heart, brain or bone marrow [ 17 ]. Therefore, throughout evolution, several non-cluster chemokines have participated in organogenesis, and their critical functions must be conserved in order for the species to survive. Thus, evolutionary pressure selects against changes in these genes by preventing them from diverging from their original function.
In contrast to the cluster chemokines, the non-cluster and mini-cluster chemokines have been conserved throughout evolution and are therefore thought to be more 'ancestral' genes. This prediction is also supported by the phylogenetic tree shown in Figure 2 , in which non-cluster and mini-cluster chemokines branch much earlier than the major-cluster chemokines and each human chemokine of this type has a clearly identifiable mouse counterpart [ 2 ].
There are data to support this model. Two groups have reported that, in the zebrafish, the CXCLCXCR4 pair regulates the homing of primordial germ cells to the gonads, where they differentiate into gametes [ 19 , 20 ]. Identical amino acid residues are highlighted in green; the seven transmembrane regions of the receptors are indicated by black lines; the four conserved cysteine residues are indicated by dots above the sequences.
Species abbreviations: dare, Danio rerio zebrafish ; pema, Petromyzon marinus sea lamprey ; lafl, Lampetra fluviatilis European river lamprey. The zebrafish genome contains many other chemokine genes, including those with the GenBank accession numbers NM and NM[ 21 ], yet, in contrast to CXCL12, the correspondence of these molecules with human chemokines is not easy to establish.
GenBank now includes many chemokine gene entries from various genomes, including many mammals, shark, fish including zebrafish and even what may be homologs of chemokine receptor genes in Caenorhabditis elegans [ 22 ]. This interspecies genomic analysis will eventually help us understand the evolutionary history of the chemokine superfamily and may even allow us to identify a 'primordial' chemokine gene.
It should be interesting to identify what the original function of this ancestral chemokine gene could have been. Another area of intense research is the function of chemokines in the development and function of the central nervous system [ 24 ]. This primary function in cellular traffic in vivo also supports a role for chemokines in cancer metastasis [ 25 ].
Recently, Balabanian et al. The sequence and characteristics of this receptor indicate that it belongs to the CXC receptor family and, as such, it should be named CXCR7. Its expression is more restricted than that of CXCR4, and it will be interesting to characterize its function in detail.
The evolution of the chemokines is an ongoing process, and there are examples of ligands forming 'mini-clusters' as well as major clusters Figure 2b. Thus, it is possible that CCL27 was originally located in chromosome 5p12 and may have translocated to its present site. Alternatively, the location of the CCL27 gene could be explained by the fact that the gene for the 3 chain of the interleukin 11 receptor is located on this site but in opposite orientation [ 30 ], indicating that this locus has been subjected to multiple evolutionary forces.
Further evidence that chemokine evolution is ongoing is provided by XCL1 and XCL2 previously called lymphotactin , which are the result of a recent gene duplication as they only differ by one amino acid [ 31 ] and they share the receptor XCR1 [ 32 ] Figure 3b , Table 1. Another example in the mouse is Ccl21, which is encoded by three different genes that differ in one amino acid codon and are expressed in distinct anatomical locations [ 33 ]. The mouse is generally considered a valuable model for human diseases.
The completion of the mouse genome supports this view, because it seems to be remarkably similar to the human genome [ 34 ]. Analysis of the human and mouse genomes has revealed that the genes involved in immune and host defense roles are under positive selection pressure, accumulating amino acid changes more rapidly than other genes.
Chemokines are listed as one of the eight most rapidly changing proteins and domains [ 35 ]. Examination of the gene organization of human and mouse chemokine clusters also shows great divergence Figure 3 [ 36 ]. The following are three important differences. First, some chemokine genes exist in one species but not the other. Alternatively, a given gene in one species for example, CCL16 and CCL18 may be represented by a pseudogene in the other. Second, a given chemokine may be related to or represented by more than one ortholog in the other species Table 1.
This is due to independent duplication events that have occurred in one of the species. Third, there can be similar genes in the two species but they may not be 'exact' structural or functional equivalents. One of the best examples of the latter is the MCP group. Structurally, it is difficult to assign a human counterpart unambiguously to each mouse gene, because they are all closely related molecules that probably arose independently in each species Figure 2a.
Differences like these may result in important differences in the function of chemokines between species. These potential differences do not, however, exclude the mouse as a valid model for human disease.
But they do mean that there are limitations to the extrapolations we can make when using mouse models to understand human disease. Figure 1. Functional roles of chemokines in response to viral infection of the CNS. Chemokines and Neuroprotection during Viral Infection Although early signaling events are clearly important for host defense during viral infection, the infiltration and anti-viral activity of T lymphocytes are requisite for viral clearance and survival. Chemokines and Neuropathology following Viral Infection A potential consequence of chemokine secretion and the subsequent accumulation of leukocytes within the CNS, while important for viral control in many instances, is the development of neuropathology.
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Chemokines Signaling Pathway - Creative Diagnostics
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The chemokine ligand and receptor superfamilies
Bibcode : Natur. Bibcode : Sci Experimental Biology and Medicine. Bibcode : PNAS Cell signaling : cytokines. Chemokine receptor modulators. Agonists: CCL Agonists: CXCL Agonists: Chemerin Resolvin E1. Categories : Cytokines Signal transduction. Hidden categories: Articles needing additional references from April All articles needing additional references.
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