Route of diapedesis. (A) The paracellular route. Paracellular migration is associated with the disruption of the EC junction to form a gap through which the cells migrate, and it involves the sequential engagement of several adhesive receptors, some of which are recruited to the EC plasma membrane via the LBRC. Paracellular migration is favored when the EC content in stress fibers is high, which helps open EC junctions. (B) The transcellular route. During transcellular migration, EC junctions remain intact. Instead, neutrophil-EC contacts fuse (represented in dark red) and remodel into a transcellular channel forming a path for leukocytes. This necessitates the recruitment of an actin-rich membrane, ICAM-enriched caveola, and vesicle vesicular vacuolar organelles (VVO) as well as the recruitment of various adhesive molecules via the LBRC. Several signaling mechanisms important for invasive protrusions and transcellular have been identified. High ICAM density, high integrin signaling, low Rap1b/Tiam1, and subsequent high PI3K/Akt signaling trigger neutrophil invasive protrusions and transcellular migration. CD2AP in ECs destabilizes ICAM clusters and limits transcellular migration. Transcellular migration is favored when the EC content in stress fibers is low but the EC junctions are tight. ESAM, endothelial cell–selective adhesion molecule.