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  • br Acknowledgements br Introduction Chemokines are a superfa

    2019-07-10


    Acknowledgements
    Introduction Chemokines are a superfamily of chemotactic cytokines that play important roles in regulating cell migration and activation under inflammatory conditions (Nomiyama et al., 2008; Peatman and Liu, 2007; Zlotnik and Yoshie, 2000), such as angiogenesis (Arenberg et al., 1997; Keane et al., 1998), neurological development (Gordon et al., 2009; Belmadani et al., 2006), organogenesis and germ cell migration (Doitsidou et al., 2002; Knaut et al., 2003). Moreover, the chemokine superfamily consists of important immune components that link innate and adaptive immunity (Alejo and Tafalla, 2011). Specifically, chemokines promote leukocyte mobilization and regulate immune responses and differentiation in recruited cells (Alejo and Tafalla, 2011; Esche et al., 2005). Chemokines are structurally related small peptides, and the majority of these peptides contain four conserved cysteine residues (Peatman and Liu, 2007; Chen et al., 2013). Chemokines are divided into four subfamilies according to the positions of these four conserved N-terminal cysteines: CXC, CC, C and CX3C (Bao et al., 2006). The CXC subfamily is highly important immunologically. Chemokine receptors are a large superfamily of G protein-coupled receptors containing 7 transmembrane domains that are predominantly localized on the surface of leukocytes (Kakinuma and Hwang, 2006). These receptors contain a short acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues that act as phosphorylation sites during receptor regulation (Murdoch and Finn, 2000). The N-terminal end of a chemokine receptor is key for ligand specificity, whereas G-proteins couple to the C-terminal end, which is important for receptor signaling after ligand binding (Murdoch and Finn, 2000). Chemokine receptors are also divided into four subfamilies, CXC, CC, CX3C and XC, based on the spacing of cysteine residues near the N-terminal of the receptor (Zlotnik et al., 2006; Kakinuma and Hwang, 2006). CXC chemokine ligands (CXCL) can be classified as ELR+ or ELR− according to the presence or absence of a tri-amino Luzindole motif (Glu-Leu-Arg or E-L-R) preceding the first conserved cysteine at the N-terminus (Pisabarro et al., 2006; Matloubian et al., 2000; Wang et al., 2005). CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8 and CXCL15 are ELR+ proteins in mammals. They play an important role in promoting adhesion of neutrophils to endothelial cells; these cells are then transferred to inflammatory sites along the gradient of chemokines associated with the matrix protein and cell surface (Laing and Secombes, 2004). The ELR− chemokine group includes CXCL4, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14 and CXCL16. Most ELR− CXC chemokines are angiostatic, with anti-angiogenic characteristics; they also attract lymphocytes and monocytes (Oppenheim et al., 2000; Fernandez and Lolis, 2002). In teleost fish, the ELR motif is sometimes replaced by a DLR motif (Asp-Leu-Arg). Although it was initially thought that this conservative change from E to D did not affect function (Hebert et al., 1991), recent studies have shown that the DLR motif is not necessary for neutrophil attraction to CXC chemokines (Cai et al., 2009). To date, six different CXC clades have been found in teleost fish: CXCa, CXCb, CXCc, CXCd, CXCL12 and CXCL14 (Huising et al., 2003, 2004). However, not all fish contain these six clades of CXC chemokine genes. For example, CXC chemokines belonging to the CXCc clade are only found in carp (Cyprinus carpio) (Chen et al., 2013; Huising et al., 2003), whereas rainbow trout (Oncorhynchus mykiss) possesses CXC chemokines belonging to the CXCa and CXCb, CXCL12, and CXCL14 clades as well as the fish-specific CXCd clade (Chen et al., 2013; Wiens et al., 2006). Luzindole In contrast, over 100 chemokine genes have been reported in zebrafish (Nomiyama et al., 2008). Compared to chemokine ligands, chemokine receptors are relatively conserved among species, especially among mammals (Nomiyama et al., 2011), with only 6 CXC chemokine receptor (CXCR) genes have been identified in the human and mouse genomes (Zou et al., 2015; Nomiyama et al., 2011; Zlotnik and Yoshie, 2012). In contrast, 8 CXCR genes have been reported in zebrafish and channel catfish (Zou et al., 2015; Fu et al., 2017a, 2017b). Chemokine receptors can often bind more than one chemokine ligand, and a single chemokine ligand often binds to more than one receptor. This binding promiscuity is one of the characteristics of the chemokine system and is primarily observed for inflammatory chemokines and their receptors. Therefore, interaction between chemokines and receptors plays an important role in immune cell differentiation, development and directional migration.