CXCR1

CXCR1, or C-X-C chemokine receptor type 1, also known as interleukin-8 receptor alpha (IL-8RA) or CD128, is a G protein-coupled receptor (GPCR) primarily expressed on neutrophils and epithelial cells. It binds to chemokines such as IL-8 (CXCL8) and GRO-α (CXCL1), mediating chemotaxis and activation of immune cells during inflammatory responses. Ligand binding induces conformational changes leading to G protein activation, triggering downstream pathways including MAPK, PI3K/Akt, and JAK/STAT. These pathways regulate cell migration, survival, and degranulation. CXCR1 is central to neutrophil recruitment in acute inflammation and tissue repair, while its dysregulation is implicated in chronic inflammatory diseases and cancer progression.
Elevated CXCR1 signaling is associated with rheumatoid arthritis, inflammatory bowel disease, and tumor metastasis, particularly in breast and colorectal cancers. Its role in tumor-associated neutrophil infiltration makes it a therapeutic target. Small-molecule antagonists (e.g., reparixin) and monoclonal antibodies targeting CXCR1/2 have shown efficacy in preclinical models by blocking IL-8-driven inflammation and angiogenesis. Clinical trials are evaluating these inhibitors in combination with chemotherapy or immunotherapy for metastatic cancers. However, challenges remain in achieving receptor specificity and minimizing immunosuppressive side effects. Recent studies also explore CXCR1's involvement in COVID-19-related cytokine storms, highlighting its broad pathophysiological relevance.