Sunday, 1 June 2008

How do leukocytes get from the blood into inflamed tissue?

This question deals with what is sometimes known as the leukocyte extravasation. It is classically divided into discrete steps, but there is little consensus on what these steps are! The version I favour is below...

1. Rolling

When a tissue is inflamed, the endothelium of its blood vessels (usually that of the post-capillary venules, where shear forces are least) expresses certain proteins on their surace called selectins. These selectins (principally P-selectin initially) bind with loose affinity to ligands on leukocytes. (For instance, P-selectin binds to PSGL-1 on leukocytes.) Since this affinity is loose, it has the effect of slowing the leukocytes down, and they now roll stutteringly along the endothelium.

How does the endothelium know to express its selectins? Resident macrophages in the tissue that happen to encounter a pathogen (or damaged tissue) secrete various cytokines in response. Some of these (e.g. IL-1 and TNF╬▒) cause the surrounding blood vessel endothelium to express their selectins.

2. Activation

Now that the leukocyte is stumbling along the wall at a slower pace than before, it has the time to receive messages (via other cytokines) from the inflamed tissue and its endothelium. Rather than simply hope the right cytokines meet the right cell, the relevant cytokines are usually presented to the leukocyte. These cytokines usually have two binding sites, one for the leukocyte (obviously) but also one that attaches it (indirectly) to the endothelium. (For instance, a common case is for the cytokine to be attached to the heparin sulphate part of an endothelial proteoglycan.) Thus, the cytokines are ready and waiting, tethered to the endothelium, for the right leukocyte to pass by.

3. (Tight) Adhesion

Why is it important for the leukocyte to be activated? Well, part of the answer lies in what it does in response. Leukocytes (and other cells) have proteins known as integrins on their surfaces. Though they bind to many things, in the context of the present discussion their aim is ultimately to bind to complementary receptors on the endothelium. The problem is that the leukocyte's integrins are in a poor-affinity state, and so they don't bind well at all. Activation of the leukocyte, however, causes them to undergo a dramatic change in shape and thus switch to a high-affinity state. With this new-found superadhesiveness, the integrins bind to receptors belonging to the immunoglobulin superfamily. Examples of the latter include intercellular cellular adhesion molecules-1 and -2 (ICAM-1 and ICAM-2) and vascular cell adhesion molecule-1 (VCAM-1). ICAM seems most involved in this step.

The result of his strong binding is to cause the rolling leukocyte to come to a complete stop on the endothelium. It is now ready for its last step.

4. Transmigration and chemotaxis

Further cytokine-based signalling cause the leukocyte to change its shape. Starting with its leading edge, it becomes flattened and much thinner, and it works with proteins on the endothelium to basically get pulled through the spaces between endothelial cells. Its final barrier is the vascular basement membrane. There is no fancy, subtle trick to bypassing this stumbling block - the leukocyte simply secretes proteases that punch a hole the basement membrane!

It is now truly within the affected tissue, and homes into its target by means of chemotactic signals. This means that, like a blood hound, it detects the direction from which certain (inflammatory) chemicals are coming from, and moves towards them.

And thus, via a number of clever steps, the leukocyte has moved from the blood stream to the exact site of injury or infection. It really is rather clever.
There's a nice Flash animation of the process to be found here.

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