Chemokine ligand–receptor binding relationships. Five subfamilies of chemokines, CXC, CC, XC, CX3C, and CX, have been recognized on the basis of the arrangement of the two N-terminal residues of four conserved cysteines. One and three amino acids separate the first and second cysteines in the CXC and CX3C chemokines, respectively, whereas the two cysteines are adjacent to each other in the CC subfamily. The XC (or C) subfamily lacks the first and paired third cysteine residues. The fifth subfamily, CX, which has so far been identified only in zebrafish, lacks one of the two N-terminal cysteine residues but retains the third and fourth (Nomiyama et al. 2008). Chemokines can also be functionally classified into several groups, based on their mode of expression and function (Zlotnik & Yoshie 2000; Moser et al. 2004; Mantovani et al. 2006). These groups are shown in different colors. Both the common names and systematic nomenclature are shown in the figure. Recently, Islam et al. (2011) showed that mouse Ccl8 serves as an agonist for Ccr8 but not for Ccr2, whereas human CCL8 binds CCR2 but not CCR8. We previously proposed that the mouse ortholog of human CCL8 is Ccl12 rather than Ccl8 (Nomiyama et al. 2003). Thus, mouse Ccl8 is now likely to be a mouse-specific gene without a human counterpart. Consistent with this, mouse Ccl12 has been shown to bind Ccr2, as does human CCL8 (Sarafi et al. 1997). Therefore, the mouse genes require renaming. The other discrepancies between human and mouse chemokine gene names are described in our previous review (Nomiyama et al. 2010). All known chemokine receptors are seven-transmembrane G protein-coupled receptors. Chemokine receptors are classified according to their ability to bind a specific subclass of chemokines (CXCR, CCR, XCR, and CX3CR) (Murphy et al. 2000). However, mouse Cxcr3 and human CX3CR1 have been shown to bind ligands of a different subclass, mouse Ccl21 (Soto et al. 1998) and human CCL26 (Nakayama et al. 2010), respectively, in addition to their cognate ligands. The receptor(s) for the CX chemokines has not yet been identified. Thus far, 18 signaling chemokine receptors have been identified in the human genome. Besides these classic chemokine receptors, five atypical (nonsignaling) chemokine receptors have been identified (DARC, CCBP2, CCRL1, CCRL2, and CXCR7) (Graham 2009; Leick et al. 2010; Naumann et al. 2010). These atypical receptors bind chemokines but do not elicit standard chemotactic responses after ligand binding. Both DARC and CCBP2 primarily bind inflammatory chemokines of the CXC and CC subfamilies. The ligand specificity of the receptors shown here may change by post-translational modification of the ligands (Mortier et al. 2008).
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