Endothelial junction regulation: a prerequisite for leukocytes crossing the vessel wall

Abstract

The leukocytes of the innate immune system, especially neutrophils and monocytes, exit the circulation early in the response to local inflammation and infection. This is necessary to control and prevent the spread of infections before an adaptive immune response can be raised. The endothelial cells and the intercellular junctions that connect them form a barrier that leukocytes need to pass in order to get to the site of inflammation. The junctions are tightly regulated which ensures that leukocytes only exit when and where they are needed. This regulation is disturbed in many chronic inflammatory diseases which are characterized by ongoing recruitment and interstitial accumulation of leukocytes. In this review, we summarize the molecular mechanisms that regulate endothelial cell-cell junctions and prevent or permit leukocyte transendothelial migration.

Fig. 1

Leukocyte adhesion and transmigration cascade. Leukocytes from the blood stream roll on selectins expressed by endothelia at sites of inflammation (1). Activation through cytokines deposited on endothelial cells leads to activation of leukocyte integrins and firm adhesion to ICAM-1 or VCAM-1 (2). Adhered leukocytes then crawl along chemotactic gradients on endothelial cells (3). Interaction with the endothelial cell, especially through ICAM-1 and VCAM-1, leads to the formation of docking structures (4) and signaling events that destabilize endothelial cell junctions and induce transmigration through endothelial cell junctions (paracellular) (5) or through the cell body (transcellular) (6). Transmigrated leukocytes can then crawl in the subendothelial space and enter the perivascular tissues (7).

Fig. 2

The three multiprotein complexes that form endothelial cell-cell junctions (not drawn to scale). (1) Endothelial adherens junctions consisting of VE-cadherin which associates with intracellular p120-catenin and β-catenin (β-cat) and protein tyrosine phosphatases, like SHP2, and kinases (not shown). (2) Tight junctions are composed of occludin, claudins (claudin-5 is endothelial specific but other claudins are also expressed) and JAM-A, JAM-B and JAM-C. On the cytoplasmic side, tight junction proteins are associated with proteins like ZO-1 and indirectly with the cytoskeleton. (3) The lateral border recycling compartment with PECAM-1 and CD99 (JAM-A can also be found in the lateral border recycling compartment) underlies the adjoining cell membranes and transports the proteins from the abluminal to the apical and lateral sides where the proteins can interact with proteins on adjacent cells or form contacts with transmigrating cells.