Neutrophil transendothelial migration hotspots – mechanisms and implications

Abstract

During inflammation, leukocytes circulating in the blood stream exit the vasculature in a process called leukocyte transendothelial migration (TEM). The current paradigm of this process comprises several well-established steps, including rolling, adhesion, crawling, diapedesis and sub-endothelial crawling. Nowadays, the role of the endothelium in transmigration is increasingly appreciated. It has been established that leukocyte exit sites on the endothelium and in the pericyte layer are in fact not random but instead may be specifically recognized by migrating leukocytes. Here, we review the concept of transmigration hotspots, specific sites in the endothelial and pericyte layer where most transmigration events take place. Chemokine cues, adhesion molecules and membrane protrusions as well as physical factors, such as endothelial junction stability, substrate stiffness, the presence of pericytes and basement membrane composition, may all contribute to local hotspot formation to facilitate leukocytes exiting the vasculature. In this Review, we discuss the biological relevance of such hotspots and put forward multiple mechanisms and factors that determine a functional TEM hotspot.

Transendothelial migration induces differential migration dynamics of leukocytes in tissue matrix

“…To demonstrate the three different steps of the TEM cascade, we imaged in more detail the wall of the vessel and were able to observe the full TEM process, i.e., rolling, adhesion, and diapedesis (Figure 3H, Supplemental Video 1-2). In the video 2 neutrophils transmigrate at the same spot, shortly after each other, indicating the possible presence of a transmigration hotspot (Grönloh, Arts and van Buul, 2021). Quantification showed that the distance neutrophils travelled from the vessels into the matrix ranging from −18 μm (in the lumen) to 286 μm into the matrix (Figure 3F).…”

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“…The vascular system includes endothelial cells, contractile smooth muscle cells and pericytes at the capillary level. There is continuous communication between pericytes and vascular endothelial cells that maintain vessel wall integrity, but also contribute to regulating inflammatory and immune processes (reviewed in Grönloh) [ 15 ]. There are chemical and physical interactions that include pericyte invagination, gap junction-based interactions, adherans junction-based interactions and cell–cell adhesion (reviewed in Dessalles) [ 16 ].…”

Endothelial transmigration hotspots limit vascular leakage through heterogeneous expression of ICAM1

“…The existence of TEM hotspots has been recognized in vivo 11 , but there is no evidence for their biological relevance, nor is there clear consensus on the mechanism for hotspot recognition by leukocytes 12 . In this work, we use live-imaging and newly developed computational methods for the analysis of hotspots, providing new insight that addresses these questions.…”

“…Intravital microscopy revealed that neutrophil migration through the endothelial monolayer and the basement membrane and pericyte sheath does not occur randomly, but in fact occurs at predefined exit sites, called "hotspots" 11 . Although it is without a doubt that leukocytes use hotspots to cross the endothelium and many factors have been proposed to determine hotspot composition and localization 12 , the physiological relevance why leukocytes would prefer to cross the endothelium at hotspots is unclear. Examples of hotspot regulators are heterogenous chemokine gradients 13,14 , differences in substrate stiffness 15,16 , junction phenotype 17 and recently reported varying junctional membrane protrusion activities between individual endothelial cells 18 and autophagy at junction regions 19 .…”