Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation

Philipp Von Hundelshausen, Stijn M. Agten, Veit Eckardt, Xavier Blanchet, Martin M. Schmitt, Hans Ippel, Carlos Neideck, Kiril Bidzhekov, Julian Leberzammer, Kanin Wichapong, Alexander Faussner, Maik Drechsler, Jochen Grommes, Johanna P. Van Geffen, He Li, Almudena Ortega-Gomez, Remco T.A. Megens, Ronald Naumann, Ingrid Dijkgraaf, Gerry A.F. NicolaesYvonne Döring, Oliver Soehnlein, Esther Lutgens, Johan W.M. Heemskerk, Rory R. Koenen, Kevin H. Mayo, Tilman M. Hackeng, Christian Weber

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


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 a-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.

Original languageEnglish (US)
Article numbereaah6650
JournalScience Translational Medicine
Issue number384
StatePublished - Apr 5 2017

Bibliographical note

Funding Information:
This study was supported by Deutsche Forschungsgemeinschaft (DFG) (SFB1123-A1 to C.W. and Y.D., SFB1123-A2 to P.v.H. and R.R.K., SFB1123-A6 to O.S. and M.D., SFB1123-B5 to Y.D. and O.S., SFB1123-Z1 to R.T.A.M., SFB914-B08 to O.S. and C.W., and INST 409/150-1 FUGG to C.W. and R.T.A.M.), the European Research Council (ERC Advanced Grants nos. 249929 and 692511 to C.W.), Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) (VICI project no. 91810606 to C.W. and VIDI projects nos. 91712303 to O.S. and 91712358 to R.R.K.), Fondation Leducq [Transatlantic Network of Excellence CVGeneF(x) to C.W.], and project INCOAG from the Center for Translational Molecular Medicine to J.W.M.H. C.W. holds a van de Laar professorship at the Cardiovascular Research Institute Maastricht, Maastricht, Netherlands

Publisher Copyright:
© 2017 The Authors.


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