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Endothelial transmigration hotspots limit vascular leakage through heterogeneous expression of ICAM‐1

Upon inflammation, leukocytes leave the circulation by crossing the endothelial monolayer at specific transmigration “hotspot” regions. Although these regions support leukocyte transmigration, their functionality is not clear. We found that endothelial hotspots function to limit vascular leakage dur...

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Detalles Bibliográficos
Autores principales: Grönloh, Max L B, Arts, Janine J G, Palacios Martínez, Sebastián, van der Veen, Amerens A, Kempers, Lanette, van Steen, Abraham C I, Roelofs, Joris J T H, Nolte, Martijn A, Goedhart, Joachim, van Buul, Jaap D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827561/
https://www.ncbi.nlm.nih.gov/pubmed/36382783
http://dx.doi.org/10.15252/embr.202255483
Descripción
Sumario:Upon inflammation, leukocytes leave the circulation by crossing the endothelial monolayer at specific transmigration “hotspot” regions. Although these regions support leukocyte transmigration, their functionality is not clear. We found that endothelial hotspots function to limit vascular leakage during transmigration events. Using the photoconvertible probe mEos4b, we traced back and identified original endothelial transmigration hotspots. Using this method, we show that the heterogeneous distribution of ICAM‐1 determines the location of the transmigration hotspot. Interestingly, the loss of ICAM‐1 heterogeneity either by CRISPR/Cas9‐induced knockout of ICAM‐1 or equalizing the distribution of ICAM‐1 in all endothelial cells results in the loss of TEM hotspots but not necessarily in reduced TEM events. Functionally, the loss of endothelial hotspots results in increased vascular leakage during TEM. Mechanistically, we demonstrate that the 3 extracellular Ig‐like domains of ICAM‐1 are crucial for hotspot recognition. However, the intracellular tail of ICAM‐1 and the 4(th) Ig‐like dimerization domain are not involved, indicating that intracellular signaling or ICAM‐1 dimerization is not required for hotspot recognition. Together, we discovered that hotspots function to limit vascular leakage during inflammation‐induced extravasation.