Targeting platelet-derived CXCL12 impedes arterial thrombosis

Leberzammer, Julian; Agten, Stijn M.; Blanchet, Xavier; Duan, Rundan; Ippel, Hans; Megens, Remco T. A.; Schulz, Christian; Aslani, Maria; Duchene, Johan; Doring, Yvonne; Jooss, Natalie J.; Zhang, Pengyu; Brandl, Richard; Stark, Konstantin; Siess, Wolfgang; Jurk, Kerstin; Heemskerk, Johan W. M.; Hackeng, Tilman M.; Mayo, Kevin H.; Weber, Christian und Hundelshausen, Philipp von (2022): Targeting platelet-derived CXCL12 impedes arterial thrombosis. In: Blood, Bd. 139, Nr. 17: S. 2691-2705

Abstract

The prevention and treatment of arterial thrombosis continue to be clinically challenging, and understanding the relevant molecular mechanisms in detail may facilitate the quest to identify novel targets and therapeutic approaches that improve protection from ischemic and bleeding events. The chemokine CXCL12 augments collagen-induced platelet aggregation by activating its receptor CXCR4. Here we show that inhibition of CXCR4 attenuates platelet aggregation induced by collagen or human plaque homogenate under static and arterial flow conditions by antagonizing the action of platelet-secreted CXCL12. We further show that platelet-specific CXCL12 deficiency in mice limits arterial thrombosis by affecting thrombus growth and stability without increasing tail bleeding time. Accordingly, neointimal lesion formation after carotid artery injury was attenuated in these mice. Mechanistically, CXCL12 activated via CXCR4 a signaling cascade involving Bruton's tyrosine kinase (Btk) that led to integrin alpha IIb beta 3 activation, platelet aggregation, and granule release. The heterodimeric interaction between CXCL12 and CCL5 can inhibit CXCL12-mediated effects as mimicked by CCL5-derived peptides such as [VREY](4). An improved variant of this peptide, i[VREY](4), binds to CXCL12 in a complex with CXCR4 on the surface of activated platelets, thereby inhibiting Btk activation and preventing platelet CXCL12-dependent arterial thrombosis. In contrast to standard antiplatelet therapies such as aspirin or P2Y(12) inhibition, i[VREY](4) reduced CXCL12-induced platelet aggregation and yet did not prolong in vitro bleeding time. We provide evidence that platelet-derived CXCL12 is involved in arterial thrombosis and can be specifically targeted by peptides that harbor potential therapeutic value against atherothrombosis.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-4971
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198