CXCR

CXCR stands for C-X-C chemokine receptor, a family of seven-transmembrane G protein-coupled receptors that detect C-X-C motif chemokines and regulate leukocyte trafficking, inflammation, and immune surveillance. The CXCR family comprises several members with distinct ligand specificities, including CXCR1 and CXCR2 (bind several CXC chemokines such as IL-8/CXCL8), CXCR3 (binds CXCL9, CXCL10, and CXCL11), CXCR4 (binds CXCL12/SDF-1), CXCR5 (binds CXCL13), and CXCR6 (binds CXCL16). Atypical receptor CXCR7, also known as ACKR3, binds CXCL12 and CXCL11 but largely functions as a chemokine scavenger and modulator of CXCR4 signaling rather than a conventional signaling receptor.

Physiological roles of CXCRs include guiding leukocyte migration during development and immune responses, directing neutrophil and T cell trafficking, and contributing to angiogenesis and tissue remodeling. CXCR1/2 are especially involved in neutrophil recruitment, while CXCR3 mediates T cell migration to inflammatory sites and to secondary lymphoid organs. CXCR4 plays a critical role in hematopoietic stem cell homing and organ development; CXCR5 directs B cells to lymphoid follicles, and CXCR6 participates in memory T cell localization.

Signaling and regulation: most CXCRs couple to Gαi proteins, lowering cAMP and activating downstream pathways such as calcium signaling, MAPK, and PI3K. Receptor activity is tightly regulated by desensitization mechanisms involving GRKs and beta-arrestins, with receptor internalization and, in some cases, receptor dimerization altering signaling output. CXCR7/ACKR3 primarily scavenges chemokines and can modulate CXCR4 responsiveness through noncanonical signaling.

Clinical relevance: dysregulation of CXCR signaling is linked to inflammatory diseases, autoimmunity, cancer progression, and metastasis. CXCR4 is an HIV-1 coreceptor for X4-tropic viruses. Therapeutic targeting includes CXCR4 antagonists such as plerixafor (AMD3100), used to mobilize hematopoietic stem cells, and various CXCR antagonists under investigation for cancer and inflammatory disorders.