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  • Review Article
  • Published:

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 Gi-proteins, activation of phospholipase C, which is followed by Ca2+ release from intracellular stores and Ca2+ 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 α6β1-integrin, which enables them to migrate through the basement membrane and into adjacent tissues.

Abstract

Neutrophil recruitment, lymphocyte recirculation and monocyte trafficking all require adhesion and transmigration through blood-vessel walls. The traditional three steps of rolling, activation and firm adhesion have recently been augmented and refined. Slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration are now recognized as separate, additional steps. In neutrophils, a second activation pathway has been discovered that does not require signalling through G-protein-coupled receptors and the signalling steps leading to integrin activation are beginning to emerge. This Review focuses on new aspects of one of the central paradigms of inflammation and immunity — the leukocyte adhesion cascade.

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Figure 1: The updated leukocyte adhesion cascade.
Figure 2: GPCR-dependent LFA1 activation.
Figure 3: Transmigration.

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Acknowledgements

K.L. is funded by the National Institutes of Health. S.N. is funded by the Wellcome Trust UK and the British Heart Foundation. We wish to thank M.-B. Voisin for his contribution to Fig. 3. M.C. is a Career Investigator of the Heart and Stroke Foundation of Ontario and is funded by the Canadian Institutes of Health Research.

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Glossary

Combinatorial specificity

Specificity achieved in a sequential cascade. If there are 3 rolling molecules, 15 chemokines and 2 integrins, theoretically, 90 (3 × 15 × 2) specificities are possible.

Slow rolling

Rolling mediated by selectins (usually E-selectin) and integrins (usually LFA1), most commonly seen in neutrophils. Typical velocity is under 5 μm per second.

Shear stress

Shear stress (dyn per cm2) is the force exerted by the flowing blood (dyn) on each unit of area of endothelial surface (cm2).

Catch bond

A molecular bond that becomes stronger as pulling force is applied to it. By contrast, a slip bond becomes weaker.

G-protein-coupled receptor

(GPCR). A receptor that is composed of seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G proteins, which are a family of trimeric intracellular-signalling proteins with specific β- and γ-chains, and one of several α-chains.

Inside-out signalling

The process by which intracellular signalling mechanisms result in the activation of a cell-surface receptor. By contrast, outside-in signalling is the process by which ligation of a cell-surface receptor activates signalling pathways inside the cell.

LIM domains

LIM domains are named after their discovery in developmentally regulated transcription factors LIN11, ISL1 and MEC3. Each LIM domain consists of two tandem zinc fingers separated by two amino acids. LIM domains mediate protein–protein interactions and are frequently found in multiples.

Pericytes

Pericytes are cells that are 150–200 μm long and 10–25 μm wide. They express smooth-muscle-cell α-actin and form a discontinuous network wrapped around endothelial cells of almost all post-capillary venules, and exhibit large gaps between adjacent cells.

Vesiculo-vacuolar organelles

(VVOs). Focal clusters of vesicles and vacuoles in the form of 'bunches of grapes' within the cytoplasm of microvascular endothelial cells. In response to VEGF or histamine they can provide a direct link between the vascular lumen and extravascular space. This is thought to be part of the mechanism behind increased vascular permeability.

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Ley, K., Laudanna, C., Cybulsky, M. et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7, 678–689 (2007). https://doi.org/10.1038/nri2156

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