Endothelial activation is driven by macrophage-produced cytokines, particularly TNF-α, which induce the rapid externalization of granules called Weibel–Palade bodies in the endothelial cells. These granules contain preformed P-selectin, which appears on the surfaces of local endothelial cells just minutes after macrophages have responded to the presence of microbes by producing TNF-α. Shortly after P-selectin gets to the cell surface, mRNA encoding E-selectin is synthesized, and within 2 hours the endothelial cells are expressing mainly E-selectin. Both P-selectin and E-selectin interact with sulfated sialyl-LewisX, a sulfated form of a carbohydrate structure that is also an important blood group antigen. Sulfated sialyl-LewisX is present on the surface of neutrophils, and its interactions with P-selectin and E-selectin are important for neutrophil rolling on the endothelium. Mutations in enzymes involved in its synthesis, such as fucosyltransferase, cause defective sialyl-LewisX expression that results in an immunodeficiency, leukocyte adhesion deficiency type 2.
Integrins are also convenient cell-surface markers for distinguishing different cell types. Dendritic cells, macrophages, and monocytes express different integrin α chains and thus display distinct β2 integrins on their surface. The predominant leukocyte integrin on conventional dendritic cells is αX:β2, also known as CD11c:CD18 or complement receptor 4 (CR4) (see Fig. 3.29). This integrin is a receptor for the complement C3 cleavage product iC3b, fibrinogen, and ICAM-1. In contrast to conventional dendritic cells, most monocytes and macrophages express low levels of CD11c, and predominantly express the integrin αM:β2 (CD11b:CD18; CR3). However, patterns of integrin expression can vary, with some tissue macrophages, such as those in the lung, expressing high levels of CD11c:CD18. In the mouse, the two major branches of conventional dendritic cells can be distinguished by expression of CD11b:CD18: one branch characterized by high expression of CD11b:CD18,
Fig. 3.30 Phagocyte adhesion to vascular endothelium is mediated by integrins. When vascular endothelium is activated by inflammatory mediators it expresses two adhesion molecules, namely ICAM-1 and ICAM-2. These are ligands for integrins expressed by phagocytes— αM:β2 (also called CR3, Mac-1, or CD11b:CD18) and αL:β2 (also called LFA-1 or CD11a:CD18)
MOVIE 3.11
MOVIE 3.12
MOVIE 3.13 and a second branch that lacks CD11b:CD18. Plasmacytoid dendritic cells (pDCs) express lower levels of CD11c, but can be distinguished from conventional dendritic cells using other markers; human pDCs express the C-type lectin BDCA-2 (blood dendritic cell antigen 2), and mouse pDCs express BST2 (bone marrow stromal antigen), neither of which is expressed by conventional dendritic cells.
3-19 Neutrophils make up the first wave of cells that cross the blood vessel wall to enter an inflamed tissue.