Traffic of White Blood Cells

Fig 16.12  Domain architecture of proteins involved in signalling leukocyte migration.

Protrusion: subunits (derived from Gi) interact with p101 causing activation of the catalytic p110 . Tiam1 binds to PI(3)P through its PH domains. Rac1 interacts with the GEF domain. Retraction: The RGS domain of p115RhoGEF binds to the N-terminal of G 13. RhoA is loaded with GTP and interacts with the Rho-binding domain of its effector ROCK1.

The three-step process of leukocyte adhesion to endothelial cells

All these processes form part of a more general sequence of events that is now referred to as the three-step process of leukocyte adhesion to endothelial cells. Leukocytes make contact with the vascular endothelium from time to time, by the presentation of surface ligands (L-selectin, Sialyl Lewis-X, or PSGL- 1: see page 392) to receptors exposed on the endothelial cells (CD34, E- or P-selectin). These interactions tether the cells in a manner by which they can attach and then roll on the surfaces of the endothelial cells and finally detach (Figure 16.13a). Their close contact with the endothelial surface allows them to verify the presence of membrane-bound chemokines. Their integrins become

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Fig 16.13  The three-step model of leukocyte transendothelial migration.

(a) Representation of the three-step model of leucocyte transendothelial migration through the wall of a venule. This comprises (1) selectin-mediated rolling of leukocytes on the vascular endothelial cell surface, then (2) chemokine-mediated activation of integrins on the leukocytes, resulting in (3) arrest and migration through the vascular endothelial cell layer. Most leukocytes are mildly attached and just roll along on the endothelial surface. Migration is triggered by firm arrest due to local inflammation as a consequence of the release of chemokines and enhanced expression of the selectins, VCAM-1 and ICAM. (b) A molecular representation of the same three steps, with mauve (at the top) representing the leukocyte and orange (at the bottom) representing the endothelial cell. Left panel: Initial contact between the two cells is made through P-selectin interacting with the PSGL-1. This allows the cells to roll. Centre panel: The close proximity to the endothelial cells allows detection of IL-8 by its receptor CXCR2. This causes activation of GTP-binding proteins that in turn activate the integrin L 2. Right panel: The activated integrin now binds ICAM-1 causing firm attachment of the leukocyte to the endothelial cell. This is a prerequisite for further flattening and then migration through the endothelial cell layer (see page 384 onwards). (c) Video-micrograph illustrating a rat mesenteric venule ( 40  m diameter). The blurring within the venule is due to the flow of blood. (d) Video-micrograph illustrating leukocyte accumulation into the mesenteric tissue after upstream administration of the chemokine LTB4. (e) Thin-section electron micrograph, showing a neutrophil leukocyte (multi-lobed nucleus) migrating through a layer of endothelial cells (blue) into rat mesenteric tissue. Images from Dr Sussan Nourshargh, London, UK.

activated so that they bind to ICAM-1 or VCAM-1 present at elevated levels due to the presence of inflammatory mediators so causing their arrest. They flatten and become competent to pass through the tight endothelial layer.87,88 Not all bound cells transmigrate. Some merely perch on the endothelial cell surface and then detach. Those that do succeed, pass through the basal membrane and make it right through into the tissues.

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List of Abbreviations

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Signal Transduction

Continued

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