Abacavir causes leukocyte/platelet crosstalk by activating neutrophil P2X7 receptors thus releasing soluble lectin-like oxidized low-density lipoprotein receptor-1

Br J Pharmacol. 2023 Jun;180(11):1516-1532. doi: 10.1111/bph.16016. Epub 2023 Jan 18.

Abstract

Background and purpose: Abacavir, an antiretroviral drug used in HIV therapy associated with myocardial infarction, promotes thrombosis through P2X7 receptors. The role of platelets as pro-thrombotic cells is acknowledged whereas that of neutrophils-due to their secretory capacity-is gaining recognition. This study analyses the role of neutrophils-specifically the secretome of abacavir-treated neutrophils (SNABC )-in platelet activation that precedes thrombosis.

Experimental approach: Effects of abacavir or SNABC on platelet activation and platelet-leukocyte interactions and expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were analysed by flow cytometry. The secretome was analysed by proteomics. The role of leukocytes in the actions of abacavir was evaluated in a mouse model of thrombosis.

Key results: Abacavir induced platelet-leukocyte interactions, not directly via effects of abacavir on platelets, but via activation of neutrophils, which triggered interactions between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1 (PSGL-1). SNABC stimulated platelet activation and platelet-leukocyte interactions through a process that was dependent on LOX-1, neutrophil P2X7 and platelet P2Y1, P2Y12 and P2X1 receptors. Abacavir induced the expression of LOX-1 on neutrophils and of the soluble form of LOX-1 (sLOX-1) in SNABC . Neutrophils, LOX-1, P2X7, P2Y1, P2Y12 and P2X1 receptors were required for the pro-thrombotic actions of abacavir in vivo.

Conclusion and implications: Neutrophils are target cells in abacavir-induced thrombosis. Abacavir released sLOX-1 from neutrophils via activation of their P2X7 receptors, which in turn activated platelets. Hence, sLOX-1 could be the missing link in the cardiovascular risk associated with abacavir.

Keywords: LOX-1; P2X7 receptors; abacavir; platelet-neutrophil crosstalk; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets
  • Mice
  • Neutrophils*
  • P-Selectin
  • Receptors, Purinergic P2X7 / metabolism
  • Scavenger Receptors, Class E
  • Thrombosis* / metabolism

Substances

  • Receptors, Purinergic P2X7
  • Scavenger Receptors, Class E
  • abacavir
  • P-Selectin