Abstract
Proinflammatory cytokines such as TNF-α or IL-1β activate the endothelium promoting leukocyte transendothelial migration (TEM) via expression of cell adhesion molecules (CAM) and cause actin remodelling. However, the function of endothelial actin remodelling in TEM remains elusive, despite its involvement in the formation of docking structures, diapedesis pores and pore resealing. Here, we establish EPLIN-isoforms, EPLIN-β and EPLIN-α, as differential regulators of TNF-α-inducedactin-remodelling significantly affecting TEM. We find EPLIN-β-induced stress fiber formation upon TNF-α-treatment weakens endothelial junctions, upregulates junctional dynamics and facilitates intercellular gaps for TEM. Increased junctional dynamics involves branched actin filaments under the control of EPLIN-α, including docking structure formation and transmigratory pore closure. We further establish by EPLIN deletion and re-expression studies that EPLIN-α-mediated termination of branched actin filaments maintains TNF-α-induced junctional dynamics and intercellular gaps facilitating TEM. These findings highlight the critical role of TNF-α-induced differential actin dynamics, controlled by EPLIN isoforms, in TEM. These results also offer a wider understanding of inflammation-induced TEM by incorporating altered junctional dynamics alongside upregulation of cell adhesion molecules.
Keywords:
Actin binding proteins; Arp2/3 complex; Cell junction dynamics; JAIL; Lamellipodia; Membrane stiffness; Stress fibres; Transendothelial migration; VE-cadherin; VL.