2. Academic Validation
  3. Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation

Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation

  • Sci Transl Med. 2017 Apr 5;9(384):eaah6650. doi: 10.1126/scitranslmed.aah6650.
Philipp von Hundelshausen 1 2,  Stijn M Agten 3,  Veit Eckardt 1,  Xavier Blanchet 1,  Martin M Schmitt 1,  Hans Ippel 3,  Carlos Neideck 1,  Kiril Bidzhekov 1,  Julian Leberzammer 1,  Kanin Wichapong 3,  Alexander Faussner 1,  Maik Drechsler 1,  Jochen Grommes 4,  Johanna P van Geffen 3,  He Li 1,  Almudena Ortega-Gomez 1,  Remco T A Megens 1,  Ronald Naumann 5,  Ingrid Dijkgraaf 3,  Gerry A F Nicolaes 3,  Yvonne Döring 1 2,  Oliver Soehnlein 1 2 6,  Esther Lutgens 1 2 7,  Johan W M Heemskerk 2,  Rory R Koenen 1 3,  Kevin H Mayo 3 8,  Tilman M Hackeng 3,  Christian Weber 9 2 3
Affiliations

Affiliations

  • 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.
PMID: 28381538 DOI: 10.1126/scitranslmed.aah6650
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.

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