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In contrast to chordates, authentic chemokine and receptor orthologues can be found in the agnathan fishes (Bajoghli, 2013, Kuroda et al., 2003, Nomiyama et al., 2011, Nomiyama et al., 2013); sea lamprey has at least five chemokine receptor genes, one CXCR4 (Ensembl Acc. No.: ENSPMAP00000007678) (Kuroda et al., 2003, Zlotnik et al., 2006), two ACKR3s/CXCR7s (Ensembl Acc. Nos.: ENSPMAP00000011187 and ENSPMAP00000011401), one related to CXCR1/2, CCR6 and CCR9 (Ensembl Acc. No.: ENSPMAP00000011202) and one related to CXCR3 and CCR4 (Ensembl Acc. No., ENSPMAP00000011160) (Table 2). In river lamprey (Lampetra fluviatilis), an orthologue of CXCL8 has been characterised and is expressed in lymphocyte like Protease Inhibitor Library mass (Najakshin et al., 1999), and its candidate receptor(s) could be one of the homologous receptor genes found in sea lamprey. Agnathans are proposed to have undergone the 1R whole genome duplication followed by an additional lineage specific genome duplication (Caputo Barucchi et al., 2013, Lagman et al., 2013, Mehta et al., 2013) and have a non-canonical adaptive immune system based upon leucine-rich repeat containing receptors (Cooper and Herrin, 2010). It can be hypothesised that the emergence of the chemokine system might be associated with this major evolutionary change in immune defences, to regulate the diverse populations of immune cells appearing at this time (DeVries et al., 2006). The co-appearance of CXCR4/ACKR3 and inflammatory CXCRs in agnathans suggests that CXCR4/ACKR3 and inflammatory chemokine receptors may have emerged as a result of the 1R whole genome duplication event (Fig. 4). Many CXCR genes in teleosts have been duplicated, by either the 3rd whole genome duplication that occurred in basal teleosts and/or random duplication; at least two copies of CXCR1, CXCR3, CXCR4 and ACKR3/CXCR7 genes are present (Fig. 1 and Supplementary file 4). Their subfunctionalization is expected to be complex.
It has been well established that the jawed vertebrates have developed a complex CXC chemokine system to adapt to the emergence of the RAG-mediated adaptive immune system and the rapid expansion of lymphocyte subpopulations. In elephant shark, CXC chemokines and receptors identified recently include CXCL8, CXCL12, CXCL14 and CXCL16, CXCR1/2, CXCR3–6, and ACKR2–4 (Venkatesh et al., 2014) (Fig. 1). CXCL8 and CXCR1/2(IL-8R) have also been reported in other cartilaginous fish species (Goostrey et al., 2005, Inoue et al., 2003, Kuroda et al., 2003). In addition to the CXC system, several CC chemokines (CC19, 20, 24 and 25) and CCRs (CCR4, 6, 7 and 9) are also confirmed to be present in the C. milii genome (Venkatesh et al., 2014), suggesting a well developed chemokine network in the cartilaginous fish.
Introduction Chemokines are small polypeptides with chemotactic activity for leukocytes. Up to date, more than 40 chemokines have been described. They share tertiary structure stabilized by four cysteine residues that form disulphide bonds. Four subfamilies can be classified according to the cysteine motif (CXC, CC, C, CX3C). CXC chemokines can be further subdivided into ELR (Glu-Leu-Arg)-containing and non-ELR-containing chemokines depending on the presence of an ELR motif, which is an essential structural element for neutrophil activation, just prior to CXC structure , , . IL-8/CXCL8, GRO-α/CXCL-1, ENA-78/CXCL-5 and GCP-2/CXCL-6 are ELR (+) CXC chemokines which mainly attract neutrophils to inflamed tissues. Therefore, CXC chemokines such as PF4/CXCL4, IP10/CXCL10, MIG/CXCL9 and SDF-1/CXCL12, which lack ELR sequence, are not able to activate neutrophils. Another important point for ELR (+) CXC chemokine is that they all promote neovascularization termed as the angiogenic chemokines. Except SDF-1/CXCL12, ELR (–) CXC chemokines do not have angiogenic features, and actually inhibit neovascularization, however , , , .