Getting to the site of inflammation: the leukocyte adhesion cascade updated

Key Points Leukocyte adhesion proceeds in a cascade-like fashion, starting with capture and followed by rolling and arrest. In all leukocytes, rapid arrest can be triggered by chemokines, but myeloid cells can also arrest through a chemokine-independent, selectin-dependent pathway. Leukocyte arrest requires integrin activation by inside-out signalling, a process that starts with the dissociation of heterotrimeric G i -proteins, activation of phospholipase C, which is followed by Ca 2+ release from intracellular stores and Ca 2+ influx, and activation of the guanine nucleotide exchange factor CALDAG-GEFI (calcium- and diacylglycerol-regulated GEFI). Arrest involves the small GTPases RAP1 and RHOA and other signalling elements that remain to be elucidated, including the cytoskeletal protein(s) that directly interact with leukocyte integrins. After arrest, leukocyte adhesion is strengthened through integrin clustering and outside-in signalling that involves spleen tyrosine kinase (SYK), SRC kinases, phosphoinositide 3-kinase (PI3K), VAV1, VAV2 and VAV3. Monocytes and neutrophils crawl inside the blood vessel before transmigrating. Adherent leukocytes transmigrate through the endothelial monolayer via mechanisms that involve PECAM1 (platelet/endothelial-cell-adhesion molecule), JAM-A (junctional adhesion molecule A), JAM-B and JAM-C, ESAM (endothelial cell-selective adhesion molecule), ICAM1 (intercellular adhesion molecule 1) and ICAM2, VCAM1 (vascular cell-adhesion molecule 1) and CD99. Transmigration proceeds through paracellular and transcellular routes, depending on the stimulus and vascular bed. In the transmigration process, neutrophils and probably other leukocytes alter their cell-surface phenotype, for example by expressing α 6 β 1 -integrin, which enables them to migrate through the basement membrane and into adjacent tissues.