Leukocytes use endothelial membrane tunnels to extravasate the vasculature
Posted on: 8 December 2024 , updated on: 9 December 2024
Preprint posted on 30 October 2024
No road? No problem ! Squeezing through cell tunnels helps leukocytes reach their target sites
Selected by Felipe Del Valle Batalla
Categories: cell biology, immunology
Background
Leukocytes are essential components of the immune system, tasked with reaching sites of infection or injury to combat pathogens and initiate tissue repair. To reach these sites, they must exit the bloodstream and enter the surrounding tissues, a process known as transendothelial migration (TEM). Traditionally, the paracellular route of TEM, where leukocytes squeeze between adjacent endothelial cells, was thought to involve the detachment of these endothelial cells. However, this study challenges this long-held belief by providing evidence of a more intricate and dynamic process involving the formation of endothelial membrane tunnels.
Key Findings
- Endothelial cell membranes overlap: The authors of this preprint demonstrate the existence of overlapping endothelial cell membranes (Fig.1 C&D), extending beyond the localization of VE-cadherin, both in vitro and in vivo. These overlaps were observed in various vascular beds, suggesting a widespread phenomenon.
- Actin regulation of overlaps: The width of these membrane overlaps is regulated by the actin cytoskeleton, with inhibition of actin polymerization or myosin-mediated contractility leading to a reduction in overlap area.
- Formation of TEM tunnels: High-resolution imaging techniques, including confocal and lattice light sheet microscopy, revealed the dynamic formation of tunnel-like structures, termed “TEM tunnels,” by overlapping endothelial membranes during neutrophil TEM. These tunnels are formed by the leukocyte lifting the membrane of one endothelial cell while crawling over the membrane of the adjacent cells (Fig.4 A&B).
- PECAM-1 decoration of TEM tunnels: PECAM-1, a junctional adhesion molecule, was found to be highly concentrated within the TEM tunnels, potentially supporting the transmigration process (Fig.5 C). In contrast, VE-cadherin, another junctional molecule, was excluded from the tunnel and displaced to the sides
Significance
This study presents a paradigm shift in our understanding of paracellular TEM. The discovery of endothelial membrane tunnels unveils a previously unrecognized level of complexity in leukocyte trafficking. This finding has significant implications for understanding inflammation and immune responses. By elucidating the mechanisms behind TEM tunnel formation and regulation, we may be able to develop novel therapeutic strategies to modulate immune cell trafficking in various inflammatory diseases.
Future directions and questions for the authors
-
- Can you hypothesize on the specific signaling pathways and molecular mechanisms that drive the formation and stability of these TEM tunnels. Could there be specific leukocyte-sensing from ECs that allows them to facilitate the tunnel formation?
- Do you think different leukocyte subtypes, such as monocytes and lymphocytes, utilize these tunnels during TEM?
- Can targeting the formation or function of TEM tunnels be exploited to control leukocyte trafficking in pathological conditions, such as autoimmune diseases or chronic inflammation. If so, what would be a molecular target that you think might work?
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