GPR35/CXCR8 is a New Chemokine Receptor for the Mucosal Chemokine CXCL17

Chemokines are a superfamily of chemotactic cytokines that direct the movement of cells throughout the body under homeostatic and inflammatory conditions.  Chemokines bind to G protein-coupled receptors expressed on target cells to trigger intracellular signaling cascades and induce chemotaxis.  Although the receptors of most chemokines have been identified, the receptor for the mucosal chemokine CXCL17 was still undefined.  Using a multifaceted approach we have identified GPR35 as the receptor for CXCL17, and have re-named it chemokine (C-X-C motif) receptor 8 (CXCR8).  CXCR8 is expressed in CXCL17-responsive human monocytes, dendritic cells and monocytoid cell lines.  Additionally, transfection of CXCR8 into Ba/F3 cells rendered them responsive to CXCL17 in calcium mobilization assays.  CXCR8 is preferentially expressed in mucosal tissues that mirror CXCL17’s expression.  Importantly, a Cxcl17^-/- mouse exhibits defective recruitment of mucosal macrophage populations, reduced expression of CXCR8 in mucosal tissues, and defective chemotactic responses to Cxcl17 in vitro.  We conclude that CXCR8 is a novel chemokine receptor and that these observations strongly suggest that the CXCL17-CXCR8 axis represents a novel target for therapeutic intervention in inflammatory processes of the respiratory or digestive systems.