title: Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice.
abstract: Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.
authors.affiliation: Institute for Cardiovascular Molecular Research, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.forename: Philipp
authors.initials: P
authors.lastname: von Hundelshausen
authors.forename: Irina V
authors.initials: IV
authors.lastname: Nesmelova
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Alisina
authors.initials: A
authors.lastname: Sarabi
authors.forename: Birgit K
authors.initials: BK
authors.lastname: Kramp
authors.forename: Anna M
authors.initials: AM
authors.lastname: Piccinini
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.forename: M Anna
authors.initials: MA
authors.lastname: Kowalska
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism*; D018956:CD5 Antigens / Q000235:genetics; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006949:Hyperlipidemias / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010978:Platelet Factor 4 / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D055503:Protein Multimerization / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D018925:Chemokines; D010978:Platelet Factor 4