CXCRs

CXCRs are a family of chemokine receptors that belong to the seven-transmembrane G protein-coupled receptor (GPCR) superfamily. They respond to CXC chemokines and play key roles in leukocyte trafficking, development, and tissue homeostasis. The human CXCR repertoire is commonly numbered CXCR1 through CXCR7, with some receptors forming functional axes that influence immune and nonimmune cell behavior. Atypical receptors such as CXCR7 (also known as ACKR3) can regulate chemokine availability rather than signaling in the classic GPCR manner.

Different CXCRs have distinct ligand specificities and biological roles. For example, CXCR1 and CXCR2 bind several CXC chemokines including CXCL8/IL-8 and are prominent in neutrophil recruitment. CXCR3 binds the ligands CXCL9, CXCL10, and CXCL11 and guides T cell trafficking. CXCR4 binds CXCL12 and functions in stem cell homing and HIV entry, while CXCR7/ACKR3 scavenges CXCL12 and CXCL11, shaping chemokine gradients. CXCR5 interacts with CXCL13 to organize B cell localization within lymphoid tissues, and CXCR6 binds CXCL16 to influence various inflammatory processes.

Signal transduction through CXCRs is typically Gi/o protein–coupled, leading to reduced cAMP, intracellular calcium flux, and activation of MAPK and PI3K pathways, driving cytoskeletal rearrangements and cell migration. Regulation involves receptor desensitization and internalization, often mediated by beta-arrestins, and some receptors display signaling bias.

Clinically, CXCRs are targets of interest in inflammatory diseases, cancer, and HIV infection. CXCR4 antagonists like plerixafor (AMD3100) are used to mobilize hematopoietic stem cells, illustrating the therapeutic potential of modulating CXCR signaling.