title: Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation.
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.
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Philipp
authors.identifier: 0000-0001-7474-9370
authors.initials: P
authors.lastname: von Hundelshausen
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Stijn M
authors.initials: SM
authors.lastname: Agten
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Veit
authors.identifier: 0000-0002-8786-1967
authors.initials: V
authors.lastname: Eckardt
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Blanchet
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Schmitt
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Ippel
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Carlos
authors.identifier: 0000-0002-6367-3320
authors.initials: C
authors.lastname: Neideck
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Kiril
authors.initials: K
authors.lastname: Bidzhekov
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Leberzammer
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Kanin
authors.initials: K
authors.lastname: Wichapong
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Faussner
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.affiliation: Department of Vascular Surgery, RWTH Aachen University, Aachen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Johanna P
authors.initials: JP
authors.lastname: van Geffen
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Almudena
authors.initials: A
authors.lastname: Ortega-Gomez
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Gerry A F
authors.identifier: 0000-0002-2482-0412
authors.initials: GA
authors.lastname: Nicolaes
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.|Department of Physiology and Pharmacology, Karolinksa Institutet, Stockholm, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.|Department of Medical Biochemistry, AMC, Amsterdam, Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.|Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.|Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany. chweber@med.lmu.de.|German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.|Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
authors.forename: Christian
authors.identifier: 0000-0003-4610-8714
authors.initials: C
authors.lastname: Weber
mesh_terms: D000208:Acute Disease; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization
chemical_list: D018925:Chemokines; D010455:Peptides