Cutting Edge: GPR35/CXCR8 is the Receptor of the Mucosal Chemokine CXCL17

Maravillas-Montero JL, Burkhardt AM, Hevezi PA, Carnevale CD, Smit MJ, Zlotnik A.

J Immunol. 2014 Nov 19. pii: 1401704. [Epub ahead of print]

From Left to Right: Jose Luis Maravillas-Montero, Amanda Burkhardt, Christina Carnevale and Albert Zlotnik

From Left to Right: Jose Luis Maravillas-Montero, Amanda Burkhardt, Christina Carnevale and Albert Zlotnik

Chemokines control the migration and homing of hematopoietic cells in the body. The last chemokine to be described was CXCL17, which exhibits a distinct mucosal expression pattern. It is strongly expressed in the lung, where it is expressed by epithelial cells of the trachea and bronchi, and in the digestive system in the tongue, oral cavity, stomach and intestines. It is a powerful macrophage chemoattractant, although it also induces chemotaxis of dendritic cells and granulocytes. Since it was the last chemokine ligand to be described, its cognate receptor was not known. We sought to identify the CXCL17 receptor. To this end, we first confirmed that it did not signal through known chemokine receptors, including CCR2, which is also expressed in macrophages. We then identified several orphan G-protein coupled receptors expressed by human monocytes. We further analyzed these GPCRs for two characteristics; first, the presence of structural motifs present in other chemokine receptors , and second, strong expression in mucosal tissues. These analyses let us shorten the list of CXCL17 receptor candidates. We screened these candidates by transfecting cDNAs encoding these receptors into BA/F3 cells that do not respond to CXCL17. Chemokines elicit calcium flux responses when they bind their receptors. Accordingly, we tested the BA/F3 transfected cells for the ability of CXCL17 to induce calcium fluxes in the transfected cells.  Transfection of GPR35 into BA/F3 cells rendered them responsive to CXCL17 as judged by its ability to induce calcium fluxes.  Furthermore, GPR35 exhibits a strong mucosal expression pattern and is strongly expressed in macrophages. Finally, genome wide association studies (GWAS) have shown a strong association between GPR35 and ulcerative colitis. Taken together, these results strongly suggest a role for the CXCR8/CXCL17 axis in inflammatory responses of the mucosa through their ability to recruit macrophages. PubMed:25411203