Human chemokine signaling networks are highly promiscuous. There are 25 receptors and 45 ligands in the human chemokine signaling network including seven members of the CXCR family (green), 1 XCR (cyan), 10 CCR (blue), and 1 CX3CR (violet). The CXCL chemokines are shown in shades of pink, XCL in cyan, CCL in shades of blue, and CX3CL in violet. The color intensity of the lines connecting receptors and ligands indicates the binding specificity. Darker colors indicate a higher binding affinity. There are six characterized AKCRs (orange) that antagonize the function of conventional chemokine receptors (connected with lines) by binding one or more of their ligands.

The paralogs cxcr3.2 and cxcr3.3 have antagonistic functions that regulate macrophage recruitment to sites of infection. Cxcr3.2 (orange) is a functional homolog of human Cxcr3 required for macrophage recruitment to sites of infection and other inflammatory settings. Cxcr3.3 (dark red) displays the structural of Ackrs such as the substitution of the central Arginine (R) of the highly conserved E/DRY-motif for a Cysteine (DCY) that prevents canonical GPCR signaling (arrow). Cxcr3.3 regulates Cxcr3.2-mediated macrophage recruitment through its scavenging function (blunt arrow) of Cxcl11-like chemokines (blue dots). (A) Shows how macrophages infected with M. marinum (purple rods) recruit non-infected macrophages through the secretion of Cxcl11-like chemokines to contain the bacterial infection and to clear dying macrophages in wt zebrafish larvae. (B) shows how macrophage recruitment is reduced in cxcr3.2 mutants (as an actively signaling chemokine is depleted) and how fewer macrophages become infected with M. marinum due to reduced macrophage motility, favoring the contention of mycobacterial infection. (C) shows enhanced recruitment of macrophages to sites of infection due to an exacerbated Cxcr3.2 signaling because of higher ligand availability in absence of the scavenging function of Cxcr3.3. The dissemination of mycobacteria into these newly recruited macrophages will later seed secondary granulomas, supporting the dissemination of the infection.