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Sci Transl Med. 2017 Apr 5;9(384). pii: eaah6650. doi: 10.1126/scitranslmed.aah6650.

Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation.

Author information

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
Department of Vascular Surgery, RWTH Aachen University, Aachen, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Department of Physiology and Pharmacology, Karolinksa Institutet, Stockholm, Sweden.
Department of Medical Biochemistry, AMC, Amsterdam, Netherlands.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.


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 α-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.

[Indexed for MEDLINE]

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