FIGURE 1.

The multi-step leukocyte adhesion cascade. Infection or tissue damage causes the localized release of danger signals, including cytokines, which (1) activate the endothelium causing the expression of capture receptors (P- or E-selectins), adhesion molecules (IgSF members – ICAM-1; VCAM-1) and presentation of chemokines or lipids on their surface (2) (Zhang et al., 2011). Marginated leukocytes are captured, roll along the endothelial surface until (3) they receive an activation signal (typically chemokine mediated) resulting in inside-out signaling and integrin activation (α_Lβ₂-integrin; α₄β₁-integrin) (Ley et al., 2007). This allows for stabilization of the adhesive interactions (α_Lβ₂-ICAM-1 and α₄β₁-VCAM-1 interactions) and cytoskeletal rearrangement in the leukocyte allowing (4) them to crawl over the endothelium, migrate across the endothelium (ICAM-1; JAM-1; CD31; VE-cadherin) and into the subendothelial space (Ley et al., 2007), (5) where they encounter the basement membrane and stromal compartment. This process is tightly regulated by the haemodynamic forces of the flowing blood and the stromal derived signals experienced by the endothelium (McGettrick et al., 2012). Some of the major molecules involved in this process are represented in the schematic, with molecules colored according to cell type expressing them; leukocytes = blue; endothelial cells (ECs) = red and expressed by both leukocytes and ECs = green. ICAM-1, Intracellular adhesion protein 1; IL-8, interleukin-8; JAM, junctional adhesion molecule; PECAM-1, platelet endothelial cell adhesion molecule 1; PSGL1, P-selectin glycoprotein ligand-1; VE-cadherin, vascular endothelial cadherin; VCAM-1, vascular adhesion protein 1. Created with BioRender.com.