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 language | English (US) |
|---|---|
| Article number | e20192378 |
| Journal | Journal of Experimental Medicine |
| Volume | 218 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2021 |
Funding
Disclosures: I.M. Grumbach reported grants from the National Institutes of Health, the Department of Veterans Affairs, and the American Heart Association outside the submitted work. No other disclosures were reported. This work was supported by National Institutes of Health grants R01HL046849 and HL064774 (to W.A. Muller); National Institutes of Health grants T32GM8152 and F30HL134202, and an Alpha Omega Alpha Honor Medical Society Carolyn L. Kuckein Student Research Fellowship (to P.J. Dalal); National Institutes of Health grant R01HL108932 (to I.M. Grumbach); and National Institutes of Health grant R01HL145459 (to J. Heller Brown).
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology