Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice.
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.
Koenen
Rory R
RR
Institute for Cardiovascular Molecular Research, Medical Faculty, RWTH Aachen University, Aachen, Germany.
von Hundelshausen
Philipp
P
Nesmelova
Irina V
IV
Zernecke
Alma
A
Liehn
Elisa A
EA
Sarabi
Alisina
A
Kramp
Birgit K
BK
Piccinini
Anna M
AM
Paludan
Søren R
SR
Kowalska
M Anna
MA
Kungl
Andreas J
AJ
Hackeng
Tilman M
TM
Mayo
Kevin H
KH
Weber
Christian
C
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*
D001057:Apolipoproteins E; D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D018925:Chemokines; D010978:Platelet Factor 4