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Hundelshausen, Philipp von; Agten, Stijn M.; Eckardt, Veit; Blanchet, Xavier; Schmitt, Martin M.; Ippel, Hans; Neideck, Carlos; Bidzhekov, Kiril; Leberzammer, Julian; Wichapong, Kanin; Faussner, Alexander; Drechsler, Maik; Grommes, Jochen; Geffen, Johanna P. van; Li, He; Ortega-Gomez, Almudena; Megens, Remco T. A.; Naumann, Ronald; Dijkgraaf, Ingrid; Nicolaes, Gerry A. F.; Döring, Yvonne; Soehnlein, Oliver; Lutgens, Esther; Heemskerk, Johan W. M.; Könen, Rory R.; Mayo, Kevin H.; Hackeng, Tilman M.; Weber, Christian (2017): Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. In: Science Translational Medicine, Vol. 9, No. 384, eaah6650
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Chemokines orchestrate leukocyte trafficking and function in health and disease. Heterophilic interactions between chemokines in a given microenvironment may amplify, inhibit, or modulate their activity;however, a systematic evaluation of the chemokine interactome has not been performed. We used immunoligand blotting and surface plasmon resonance to obtain a comprehensive map of chemokine-chemokine interactions and to confirm their specificity. Structure-function analyses revealed that chemokine activity can be enhanced by CC-type heterodimers but inhibited by CXC-type heterodimers. Functional synergism was achieved through receptor heteromerization induced by CCL5-CCL17 or receptor retention at the cell surface via auxiliary proteoglycan binding of CCL5-CXCL4. In contrast, inhibitory activity relied on conformational changes (in CXCL12), affecting receptor signaling. Obligate CC-type heterodimers showed high efficacy and potency and drove acute lung injury and atherosclerosis, processes abrogated by specific CCL5-derived peptide inhibitors or knock-in of an interaction-deficient CXCL4 variant. Atheroprotective effects of CCL17 deficiency were phenocopied by a CCL5-derived peptide disrupting CCL5-CCL17 heterodimers, whereas a CCL5 alpha-helix peptide mimicked inhibitory effects on CXCL12-driven platelet aggregation. Thus, formation of specific chemokine heterodimers differentially dictates functional activity and can be exploited for therapeutic targeting.