| CXCL5 and CXCL6 are ELR‑positive CXC chemokines that share the conserved CXC motif and N‑terminal glutamate–leucine–arginine sequence and act as secreted ligands for the neutrophil chemokine receptor CXCR2, with CXCL6 also engaging CXCR1 in some contexts. Their small chemokine fold, formed by an N‑terminal region, three antiparallel β‑strands, and a C‑terminal α‑helix, positions the ELR segment and key receptor‑contact residues to trigger G protein–coupled signaling when they bind CXCR2 on neutrophils and other responsive cells. Receptor engagement activates Gαi‑dependent pathways, causes calcium influx, and stimulates PI3K, ERK, and p38 MAPK cascades, which together promote integrin activation, chemotaxis, degranulation, oxidative burst, and release of additional inflammatory mediators that reinforce innate immune responses. CXCL5 is produced by epithelial cells, stromal cells, and tumor‑associated myeloid cells under the control of inflammatory cytokines and microbial or damage signals, and its expression aligns with strong neutrophil recruitment and with induction of matrix metalloproteinases such as MMP‑2 and MMP‑9 that remodel tissue barriers and extracellular matrix. CXCL6 is induced by interleukins and other inflammatory stimuli in stromal and tumor compartments and contributes to neutrophil‑rich inflammation, fibrosis, and reparative responses, and also appears in pro‑angiogenic secretomes where it supports endothelial migration and tube formation through CXCR1/2 signaling. Elevated CXCL5 and CXCL6 in synovial fluid and tissue are reported in inflammatory arthritides, where their presence is associated with neutrophil infiltration, synovial angiogenesis, and markers of persistent synovitis and joint damage. Across multiple solid tumors, CXCL5 expression correlates with higher grade and poorer prognosis, and mechanistic work links CXCL5–CXCR2 signaling to activation of ERK/Elk‑1/Snail and AKT/GSK3β/β‑catenin pathways, promotion of epithelial–mesenchymal transition, and recruitment of myeloid cells that support immunosuppressive, pro‑angiogenic microenvironments. |
