Platelet-leukocyte interactions promoting atherogenesis. (A) Platelet-mediated leukocyte recruitment and adhesion. Leukocyte recruitment to endothelial-bound platelets occurs in a multistep coordinated process. Initial tethering of leukocytes is mediated by the interaction of P-selectin expressed on the platelet surface with its cognate receptor leukocyte PSGL-1. Ligation of PSGL-1 promotes activation of leukocyte β₂ integrins (Mac-1 and LFA-1), necessary for stable leukocyte adhesion. Note that Mac-1 can engage several platelet ligands, including GPIbα, ICAM-2, and JAM-3, as well as fibrinogen bound to α_IIbβ₃. Release of the chemokine RANTES at sites of atherogenesis leads to enhanced monocyte adhesion. Monocytes subsequently migrate through the endothelium and differentiate into macrophages, which engulf lipids and transform into foam cells. (B) Platelet-leukocyte cross-talk. Bioactive mediators derived from α-granules of activated platelets, including PF4, synergize with RANTES to enhance leukocyte adhesion and monocyte differentiation. RANTES, acting in concert with P-selectin, results in MCP-1 and IL-8 secretion by monocytes. CTAP-III is another chemokine released from the platelet α-granules, which is subsequently converted into active NAP-2 by the neutrophil membrane associated serine-protease cathepsin G. NAP-2 enhances leukocyte adhesion and neutrophil transendothelial migration. Up-regulation of COX-2 in monocytes via pathways involving IL-Iβ and P-selectin results in increased production of proinflammatory mediators, including PAF, leukotrienes, and TxA₂ via transcellular eicosanoid metabolism. P-sel indicates P-selectin; AA, arachidonic acid.