Spatiotemporal restriction of endothelial cell calcium signaling is required during leukocyte transmigration

Prarthana J. Dalal, David P. Sullivan, Evan W. Weber, David B. Sacks, Matthias Gunzer, Isabella M. Grumbach, Joan Heller Brown, William A. Muller*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Endothelial cell calcium flux is critical for leukocyte transendothelial migration (TEM), which in turn is essential for the inflammatory response. Intravital microscopy of endothelial cell calcium dynamics reveals that calcium increases locally and transiently around the transmigration pore during TEM. Endothelial calmodulin (CaM), a key calcium signaling protein, interacts with the IQ domain of IQGAP1, which is localized to endothelial junctions and is required for TEM. In the presence of calcium, CaM binds endothelial calcium/calmodulin kinase IIδ (CaMKIIδ). Disrupting the function of CaM or CaMKII with small-molecule inhibitors, expression of a CaMKII inhibitory peptide, or expression of dominant negative CaMKIIδ significantly reduces TEM by interfering with the delivery of the lateral border recycling compartment (LBRC) to the site of TEM. Endothelial CaMKII is also required for TEM in vivo as shown in two independent mouse models. These findings highlight novel roles for endothelial CaM and CaMKIIδ in transducing the spatiotemporally restricted calcium signaling required for TEM.

Original languageEnglish (US)
Article numbere20192378
JournalJournal of Experimental Medicine
Volume218
Issue number1
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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