Endothelial cell VCAM‐1 regulates recruitment of lymphocytes, eosinophils, mast cells, or dendritic cells during allergic inflammation. In this report, we demonstrated that, during allergic lung responses, there was reduced zonula occludens (ZO)‐1...
Endothelial cell VCAM‐1 regulates recruitment of lymphocytes, eosinophils, mast cells, or dendritic cells during allergic inflammation. In this report, we demonstrated that, during allergic lung responses, there was reduced zonula occludens (ZO)‐1 localization in lung endothelial cell junctions, whereas there was increased lung endothelial cell expression of VCAM‐1, N‐cadherin, and angiomotin. In vitro, leukocyte binding to VCAM‐1 reduced ZO‐1 in endothelial cell junctions. Using primary human endothelial cells and mouse endothelial cell lines, Ab crosslinking of VCAM‐1 increased serine phosphorylation of ZO‐1 and induced dissociation of ZO‐1 from endothelial cell junctions, demonstrating that VCAM‐1 regulates ZO‐1. Moreover, VCAM‐1 induction of ZO‐1 phosphorylation and loss of ZO‐1 localization at cell junctions was blocked by inhibition of VCAM‐1 intracellular signals that regulate leukocyte transendothelial migration, including NOX2, PKCα, and PTP1B. Furthermore, exogenous addition of the VCAM‐1 signaling intermediate H2O2 (1 μM) stimulated PKCα‐dependent and PTP1B‐dependent serine phosphorylation of ZO‐1 and loss of ZO‐1 from junctions. Overexpression of ZO‐1 blocked leukocyte transendothelial migration. In summary, leukocyte binding to VCAM‐1 induces signals that stimulated ZO‐1 serine phosphorylation and reduced ZO‐1 localization at endothelial cell junctions during leukocyte transendothelial migration.
VCAM‐1 signaling through ROS, PKCalpha, and PTP1B induce serine phosphorylation of ZO‐1 and loss of ZO‐1 from endothelial cell junctions during VCAM‐1‐dependent leukocyte transendothelial migration.