Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability

Abstract

Many diseases have an inflammatory component, where neutrophil interactions with the vascular endothelium lead to barrier dysfunction and increased permeability. Neutrophils increase permeability through secreted products such as the chemokines CXCL1, 2, 3, and 8, through adhesion-dependent processes involving beta(2) integrins interacting with endothelial ICAM-1, and through combinations where beta(2) integrin engagement leads to degranulation and secretion of heparin-binding protein. Some neutrophil products, such as arachidonic acid or the leukotriene LTA4, are further processed by endothelial enzymes via transcellular metabolism before the resulting products thromboxane A2 or LTC4 can activate their cognate receptors. Neutrophils also generate reactive oxygen species that induce vascular leakage. This review focuses on the mechanisms of neutrophil-mediated leakage.

Figure 1

Regulation of vascular permeability by neutrophils: role of soluble mediators. Following interaction with endothelium, activated neutrophils release a variety of soluble mediators. Neutrophils help convert complement protein C5 to C5a, which binds C5a receptor (C5aR) on the endothelial cell surface. Neutrophil-secreted tumor necrosis factor α (TNFα) binds its receptors TNFR1, 2. Arachidonic acid (AA) released by neutrophils can be processed by endothelial COX-1/2 into thromboxane A2 (TXA2) and by 5-lipoxygenase (5-LO) into leukotriene A4 (LTA4). LTA4 is then metabolized by LTA4 hydrolase (LTA4H) into LTB4 or by LTC4 synthase (LTC4S) into leukotriene LTC4. TXA2 binds to the thromboxane receptor (TP) and LTC4 binds the cysteinyl leukotriene receptor subtype 2 (CysLT2R). Neutrophil-derived chemokines such as CXCL1, 2, 3, and 8 bind their endothelial receptor (CXCR2). Engagement of all these receptors leads to endothelial retraction (red arrows). Activated neutrophils also release adenosine triphosphate (ATP) though connexin 43 hemichannels (Cxn 43), which is processed by CD39 on the neutrophil surface and by CD73 on the endothelial surface to adenosine monophosphate (AMP) and adenosine (ADO), respectively. ADO binds adenosine receptors A2a or A2b blocking endothelial retraction. Unprocessed ATP or adenosine diphosphate (ADP) can couple to P2 purinoceptors (P2Y) and induce endothelial retraction. C5a and CXCL1, 2, 3, and 8 can also activate the neutrophil in an autocrine loop. Neutrophil-derived LTA4, after conversion to LTB4 by neutrophil LTA4H, activates BLT1 which can lead to release of heparin-binding protein (HBP) from adherent neutrophils and mediate increased endothelial permeability.

Figure 2

Regulation of vascular permeability by neutrophils: adhesion-dependent signals. β₂ integrins leukocyte function-associat ion antigen 1, LFA-1, and macrophage receptor 1, Mac-1 engagement with their endothelial ligands intercellular adhesion molecule 1 or 2 (ICAM-1, 2) is required for release of heparin- binding protein (HBP) from neutrophils, which binds an as yet unidentified receptor (possibly cell surface heparin sulfate proteoglycans, PG) to increase endothelial intracellular Ca²⁺. ICAM-1 engagement induces an increase in endothelial intracellular Ca²⁺ and phosphorylation of the junctional protein vascular endothelial (VE) cadherin, causing junctional disruption and cell retraction (red arrow). ICAM engagement also induces dissociation of vascular endothelial protein tyrosine phosphatase (VE-PTP, dashed arrow) from VE-cadherin, allowing for VE-cadherin phosphorylation. In addition, E-selectin engagement via P-selectin glycoprotein ligand 1 (PSGL-1) or other glycoprotein ligands induces increased endothelial intracellular Ca²⁺, extracellular signal-regulated kinase (Erk) phosphorylation, and cytoskeletal changes. As both neutrophils and endothelial cells are known to express connexins, some studies have suggested a role for gap junction formation between the two cells, however, this is still controversial.