On, around, and through: neutrophil-endothelial interactions in innate immunity

Abstract

This manuscript will review our current understanding of neutrophilic polymorphonuclear leukocyte (neutrophil) interactions with the endothelium during immune and inflammatory responses, focusing on the molecular mechanisms regulating neutrophil adhesion to and migration through the endothelium in response to infection or tissue injury. This is a complex and dynamic area of research and one that has been the topic of several recent comprehensive reviews to which the interested reader is referred (64, 118, 131). By design, this review will begin with a brief review of some basic aspects of neutrophil biology and endothelial adhesion to provide a foundation. The remainder of the review will focus on selected areas of this complex field, specifically the role of the endothelial glycocalyx in regulating neutrophil adhesion and the mechanisms and consequences of migration of neutrophils between (paracellular) and through (transcellular) endothelial cells during egress from the vasculature.

FIGURE 1. Role of the glycocalyx in regulating neutrophil adhesion to the endothelium

Endothelial surface layer (ESL) loss induces neutrophil adhesion to endothelial cells. Potential mechanisms include the release of pro-adhesion mediators previously sequestered by the glycocalyx, exposure of previously hidden endothelial surface adhesion molecules, and/or the activation (via proteoglycans) of pro-adhesion endothelial signaling pathways.

FIGURE 2. Paracellular and transcellular migration

After attaching to the endothelial surface, the neutrophil chooses whether to emigrate from the vascular space using either paracellular or transcellular routes. For paracellular migration, the neutrophil crawls along the endothelial cell surface to the intercellular junctions where it extends lamellopodia between endothelial cells, disrupting the intercellular (tight and adherens) junctions. This is followed by translocation of the entire cell through the inter-endothelial junctions. For transcellular migration, the neutrophil forms actin-rich podosomes that indent the subjacent endothelium. This is followed by the formation of actin-enriched projections by the endothelium that form a so-called “transmigratory cup” around the neutrophil. The cup is formed through the infusions of internal membranes contributed by the lateral border recycling compartment (LBRC) and/or caveolae. The contribution of the LBRC requires microtubules. Despite traversing the cytoplasm of an endothelial cell, the neutrophil causes minimal vascular leak because its route is covered by a dome formed by the endothelium.