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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Collins, Paul J. (2016)
Languages: English
Types: Doctoral thesis
Subjects: R1
The human chemokine family consists of around 50 peptides that control the migratory patterns and positioning of all leukocytes. One such member of this family is CXCL14. Very highly expressed in many healthy tissues including skin, gut and kidney, loss of CXCL14 expression in chronic inflammatory conditions and certain forms of cancer has led to a proposed role for CXCL14 in immune surveillance at these sites. The function and target cells of CXCL14 are poorly defined however, largely because the identity of its receptor remains unknown. Here, I have combined the evaluation of chemotactic responses toward CXCL14 with detection of putative CXCL14 receptor(s) on the surface of cells using a synthetic, fluorochrome-conjugated CXCL14, to definitively identify CXCL14 target cells in human. Monocytes were identified as the major target cells in peripheral blood, 28.4 ± 6.1% Monocytes migrating toward 1 µM CXCL14 in ex vivo transwell chemotaxis assays compared to 3.01 ± 0.65% toward buffer alone (p=0.0031). Responses to CXCL14 also identified tissue phagocytes extracted from healthy human skin, including an apparently novel population of skin-resident CD14+ cells characterised by lack of CD45 expression. Screening of CXCL14-responsive cells by RNA sequencing for expression of G protein-coupled receptors revealed five major candidates for the CXCL14 receptor, all of which are orphan receptors; GPR35, GPR68, GPR84, GPR141 and GPR183. At present, I am in the process of testing these candidates in functional assays. Finally, I report on a novel ability of CXCL14 to potently synergise with other chemokines, particularly CXCL12. This ‘synergy’ with CXCL12 likely occurs via a direct interaction between CXCL14 and the receptor for CXCL12, CXCR4, which is broadly expressed on immune cells. This work identifies mononuclear phagocytes in blood and tissue as the primary targets for CXCL14, providing new and exciting insights into the role played by CXCL14 in immune surveillance of peripheral tissues.

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