Neutrophil Extravasation

As an inflammatory response develops, various cytokines and other inflammatory mediators act upon the local blood vessels, inducing increased expression of endothelial CAMs. The vascular endothelium is then said to be activated, or inflamed. Neutrophils are generally the first cell type to bind to inflamed endothelium and extravasate into the tissues. To accomplish this, neutrophils must recognize the inflamed endothelium and adhere strongly enough so that they are not swept away by the flowing blood. The bound neutrophils must then penetrate the endothelial layer and migrate into the underlying tissue. Monocytes and eosinophils extravasate by a similar process, but the steps have been best established for the neutrophil, so we focus on neutrophils here.

The process of neutrophil extravasation can be divided into four sequential steps: (1) rolling, (2) activation by chemoat-tractant stimulus, (3) arrest and adhesion, and (4) transendothelial migration (Figure 15-3a). In the first step, neutrophils attach loosely to the endothelium by a low-affinity selectin-carbohydrate interaction. During an inflammatory response, cytokines and other mediators act upon the local endothe-lium, inducing expression of adhesion molecules of the selec-tin family. These E- and P-selectin molecules bind to mucin-

like cell-adhesion molecules on the neutrophil membrane or with a sialylated lactosaminoglycan called sialyl Lewisx (Figure 15-3b). This interaction tethers the neutrophil briefly to the endothelial cell, but the shear force of the circulating blood soon detaches the neutrophil. Selectin molecules on another endothelial cell again tether the neutrophil; this process is repeated so that the neutrophil tumbles end-over-end along the endothelium, a type of binding called rolling.

As the neutrophil rolls, it is activated by various chemoat-tractants; these are either permanent features of the endo-thelial cell surface or secreted locally by cells involved in the inflammatory response. Among the chemoattractants are members of a large family of chemoattractive cytokines called chemokines. Two chemokines involved in the activation process are interleukin 8 (IL-8) and macrophage inflammatory protein (MIP-1p). However, not all chemoattractants belong to the chemokine group. Other chemoattractants are platelet-activating factor (PAF), the complement split products C5a, C3a, and C5b67 and various N-formyl peptides produced by the breakdown of bacterial proteins during an infection. Binding of these chemoattractants to receptors on the neutrophil membrane triggers an activating signal mediated by G proteins associated with the receptor. This signal induces a conformational change in the integrin molecules in the neu-

Rolling

Arrest/

adhesion ©

Transendothelial migration ©

Endothelium

Arrest/

adhesion ©

Transendothelial migration ©

Endothelium

Neutrophil Extravasation

Chemokine or chemoattractant receptor

Chemokine or chemoattractant receptor

Migration Extravasation Des Monocytes

Ig-superfamily CAM

Ig-superfamily CAM

FIGURE 15-3

(a) The four sequential but overlapping steps in neutrophil extravasation. (b) Cell-adhesion molecules and chemokines involved in the first three steps of neutrophil extravasation. Initial rolling is mediated by binding of E-selectin molecules on the vascular endothelium to sialylated carbohydrate moieties on mucin-like CAMs. A chemokine such as IL-8 then binds to a G-protein-linked receptor on the neutrophil, triggering an activating signal. This signal induces a conformational change in the integrin molecules, enabling them to adhere firmly to Ig-superfamily molecules on the endothelium.

trophil membrane, increasing their affinity for the Ig-super-family adhesion molecules on the endothelium. Subsequent interaction between integrins and Ig-superfamily CAMs stabilizes adhesion of the neutrophil to the endothelial cell, enabling the cell to adhere firmly to the endothelial cell.

Subsequently, the neutrophil migrates through the vessel wall into the tissues. The steps in transendothelial migration and how it is directed are still largely unknown; they may be mediated by further activation by chemoattractants and subsequent integrin-Ig-superfamily interactions or by a separate migration stimulus.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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Responses

  • marisa
    What is the first cell that binds to inflammed endothelium?
    7 years ago
  • paciano
    When do eosinophils extravasate?
    7 years ago
  • Zachary Stewart
    Which cells are the first to bind inflamed tissue?
    7 years ago
  • finn
    What is neutophill extra vasation?
    2 years ago

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