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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

1
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
2
German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
3
Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
4
Department of Vascular Surgery, RWTH Aachen University, Aachen, Germany.
5
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
6
Department of Physiology and Pharmacology, Karolinksa Institutet, Stockholm, Sweden.
7
Department of Medical Biochemistry, AMC, Amsterdam, Netherlands.
8
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
9
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany. chweber@med.lmu.de.

Abstract

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.

PMID:
28381538
DOI:
10.1126/scitranslmed.aah6650
[Indexed for MEDLINE]

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