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The chemokine CXCL14 mediates platelet function and migration via direct interaction with CXCR4.

A. Witte,Anne-Katrin Rohlfing,B. Dannenmann,Valerie Dicenta,M. Nasri,Kyra Kolb,Jessica Sudmann,T. Castor,D. Rath,O. Borst,J. Skokowa,M. Gawaz

Published 2020 in Cardiovascular Research

ABSTRACT

AIMS Beyond classical roles in thrombosis and hemostasis, it becomes increasingly clear that platelets contribute as key players to inflammatory processes. The involvement of platelets in these processes is often mediated through a variety of platelet-derived chemokines which are released upon activation and act as paracrine and autocrine factors. In this study we investigate CXCL14, a newly described platelet chemokine and its role in thrombus formation as well as monocyte and platelet migration. Additionally, we examine the chemokine receptor CXCR4 as a possible receptor for CXCL14 on platelets. Furthermore, with the use of artificially generated platelets derived from induced pluripotent stem cells (iPSC), we investigate the importance of CXCR4 for CXCL14 mediated platelet functions. METHODS AND RESULTS In this study, we showed that CXCL14 deficient platelets reveal reduced thrombus formation under flow compared to wildtype platelets using a standardized flow chamber. Addition of recombinant CXCL14 normalized platelet-dependent thrombus formation on collagen.Further, we found that CXCL14 is a chemoattractant for platelets and mediates migration via CXCR4. CXCL14 promotes platelet migration of platelets through the receptor CXCR4 as evidenced by murine CXCR4-deficient platelets and human iPSC-derived cultured platelets deficient in CXCR4. We found that CXCL14 directly interacts with the CXCR4 as verified by immunoprecipitation and confocal microscopy. CONCLUSIONS Our results reveal CXCL14 as a novel platelet-derived chemokine that is involved in thrombus formation and platelet migration. Further, we identified CXCR4 as principal receptor for CXCL14, an interaction promoting platelet migration. TRANSLATIONAL PERSPECTIVE Interaction of CXCL14 with CXCR4 may be an important mechanism for understanding platelet function and thromboinflammation. The CXCL14/CXCR4 interaction could offer novel therapeutic strategies to control thrombosis and inflammation in inflammatory diseases such as atherosclerosis or organ ischemia. Further, the described experimental approach using genetically modified human platelets by iPS-CRISPR/Cas9 technology will be helpful for understanding platelet biology.

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