Figures & data
Figure 1. The multi-step leukocyte adhesion cascade: (1) Endothelial cells at a site of inflammation are activated by stromal derived inflammatory cytokines such as TNF-α, IL-1β and IFN-γ. Induction of transcriptional activity results in the expression of adhesion molecules and chemokines which coordinate leukocyte recruitment. (2) Leukocytes are recruited from flowing blood by specialised receptors of the selectin family and VCAM-1, which also support rolling adhesion. (3) Chemokine signals activate the β1 and β2 integrins on rolling leukocytes. (4) Adhesion is stabilised and the leukocytes become firmly adherent to the endothelial cell. (5) In response to additional signals, e.g. from PgD2, the leukocyte cytoskeleton undergoes remodelling driving shape change (spreading) and dynamic integrin-mediated migration. (6) Leukocytes migrate across and through the endothelial cell monolayer and onwards into tissue.
Figure 2. Mechanisms of platelet-mediated leukocyte recruitment: (1) appropriately activated endothelial cells express a matrix of VWF on their surface to which platelets are recruited and activated. Platelet presented P-selectin then forms an adhesive bridge between the endothelial surface and blood borne leukocytes. (2) Platelets form heterotypic aggregates with leukocytes in the circulation in a P-selectin dependent manner. Aggregates are then recruited to the VWF on the surface of appropriately activated endothelial cells. (3) Inflammatory cytokines induce transcriptional programmes in endothelial cells which result in the expression of adhesion molecules and chemokines that support leukocyte adhesion. Leukocytes in heterotypic aggregates which are recruited to the endothelial cell surface posses additional platelet borne receptors. These can in turn support the secondary adhesion of un-aggregated leukocytes. (4) Upon activation platelets shed microvesicles which bind directly to endothelial cells. Microvesicle borne inflammatory cytokines induce transcriptional programmes in endothelial cells which result in the expression of adhesion molecules and chemokines that support leukocyte adhesion. (5) P-selectin bearing PMV bind to appropriately activated endothelial cells. Platelet presented P-selectin then forms an adhesive bridge between the endothelial surface and blood borne leukocytes. (6) P-selectin bearing PMV form heterotypic aggregates with leukocytes in the circulation. Aggregates are then recruited to VWF on appropriately stimulated endothelial cells utilising microvesicle borne adhesion receptors.
Figure 3. Targets for therapeutic intervention in platelet–leukocyte adhesion and in the platelet-mediated recruitment of leukocytes: (A) Therapeutic agents that inhibit the adhesive interactions between platelets and leukocytes or which inhibit the activation of platelets by antagonising platelet derived positive feedback loops which amplify the platelet response to primary activating stimuli. (B) Therapeutic agents that inhibit platelet adhesion to the vessel wall by either antagonising adhesive pathways directly or by inhibiting endothelial cell activation in response to platelet borne activating stimuli. AA, Arachidonic acid; ADP, Adenosine diphosphate; α-G, Alpha granule; COX-1, Cyclooxygenase-1; DG, Dense granule; P2Y12, ADP receptor; PGG2, Prostaglandin G2; PSGL1, P-selectin glycoprotein ligand1; TP, Thromboxane A2 receptor; TxA2, Thromboxane A2; TxSy, Thromboxane synthase.
