Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration.
Leukocyte movement from the blood to the tissues is a fundamental process in acute and chronic inflammatory diseases. While the role of endothelial cells (EC) to recruit leukocytes to sites of inflammation is well known, the mechanisms that control remodeling of EC shape and adhesive contacts during leukocyte transendothelial migration (TEM) are not completely understood. We studied the role of IQGAP1, an adaptor protein that binds to filamentous-actin and microtubules (MT) at interendothelial junctions, during lymphocyte TEM. EC IQGAP1 knockdown decreases MT tethered to the adherens junction, and decreases lymphocyte TEM to approximately 70% (p<0.05) versus control. Similarly, loss of adherens junction-associated MT induced by brief nocodazole (ND) treatment decreases lymphocyte TEM to approximately 65% of control (p<0.01). Confocal microscopy imaging indicates that EC IQGAP1 knockdown and MT depolymerization both result in lymphocyte accumulation above the vascular endothelial cadherin (VE-cadherin) junctions and reduces the fraction of adherent lymphocytes that complete diapedesis across interendothelial cell junctions. However, we observe no change in VE-cadherin gap formation underlying adherent lymphocytes among control, IQGAP1 knockdown, or MT depolymerised EC monolayers. These data indicate that IQGAP1 contributes to MT stability at endothelial junctions. Further, IQGAP1 is involved in junction remodeling required for efficient lymphocyte diapedesis, independent of VE-cadherin gap formation.
Nakhaei-Nejad
Maryam
M
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Zhang
Qiu-Xia
QX
Murray
Allan G
AG
D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000276:immunology; D017629:Gap Junctions / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology*; D008870:Microtubules / Q000378:metabolism; D011485:Protein Binding; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D020703:ras GTPase-Activating Proteins; D000099152:Cadherin 5; C101203:IQ motif containing GTPase activating protein 1