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
  • 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. [email protected].
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.