| CXCL2, also termed MIP‑2 or GRO‑β, is a member of the ELR⁺ CXC chemokine family that functions as a potent chemotactic factor for neutrophils and other myeloid cells and contributes to early innate immune responses at sites of infection and tissue injury. The protein contains the conserved N‑terminal ELR motif and CXC chemokine fold that support high‑affinity interaction with the G protein–coupled receptor CXCR2 on neutrophils and related leukocyte subsets, and this receptor–ligand pair forms a principal axis for neutrophil recruitment. Binding of CXCL2 to CXCR2 activates Gαi‑dependent signaling, reduces cAMP, and triggers downstream pathways including PI3K, PKC isoforms, small GTPases, and MAPKs, which coordinate integrin activation, cytoskeletal remodeling, and directional migration toward CXCL2 gradients. CXCL2 also engages CXCR2‑linked signaling modules that connect to NLRP3 inflammasome activation through PKC‑μ and integrin‑linked kinase, integrating chemokine sensing with inflammasome assembly and production of inflammatory mediators in response to microbial and danger signals. In inflamed tissues, CXCL2 is produced by macrophages, neutrophils, endothelial cells, and epithelial cells and operates in concert with related ELR⁺ chemokines such as CXCL1/KC, with temporal and concentration‑dependent differences in CXCR2 activation and glycosaminoglycan binding creating complex patterns of neutrophil recruitment, retention, and egress that shape the magnitude and resolution of inflammation. CXCL2 carried by macrophage‑derived extracellular vesicles binds neutrophil CXCR2 and activates a CXCR2/PKC/NOX4 signaling axis, which enhances neutrophil recruitment and ROS‑dependent effector functions during sepsis and contributes to tissue injury when neutrophil accumulation is excessive. In the tumor microenvironment, CXCL2 produced by cancer cells, stromal cells, or infiltrating myeloid cells participates in the recruitment of neutrophils and myeloid‑derived suppressor cells, modulation of angiogenesis, and regulation of tumor growth and metastasis, and high CXCL2 expression correlates with altered prognosis and immune infiltration patterns in several malignancies. |
