IL-4 induces hyperpermeability and impairs the barrier function of human coronary artery endothelial cells by upregulating Wnt5A signaling, which mediates actin cytoskeleton remodeling.
Does IL-4 induce hyperpermeability in human coronary artery endothelial cells through Wnt5A signaling?
Wnt5A mediates IL-4 induced endothelial barrier dysfunction and hyperpermeability in human coronary artery endothelial cells.
Microvascular leakage due to endothelial barrier dysfunction is a prominent feature of T helper 2 (Th2) cytokine mediated allergic inflammation. Interleukin-4 (IL-4) is a potent Th2 cytokine, known to impair the barrier function of endothelial cells. However, the effectors mediating IL-4 induced cytoskeleton remodeling and consequent endothelial barrier dysfunction remain poorly defined. Here we have used whole genome transcriptome profiling and gene ontology analyses to identify the genes and processes regulated by IL-4 signaling in human coronary artery endothelial cells (HCAEC). The study revealed Wnt5A as an effector that can mediate actin cytoskeleton remodeling in IL-4 activated HCAEC through the regulation of LIM kinase (LIMK) and Cofilin (CFL). Following IL-4 treatment, LIMK and CFL were phosphorylated, thereby indicating the possibility of actin stress fiber formation. Imaging of actin showed the formation of stress fibers in IL-4 treated live HCAEC. Stress fiber formation was notably decreased in the presence of Wnt inhibitory factor 1 (WIF1). Non-invasive impedance measurements demonstrated that IL-4 increased the permeability and impaired the barrier function of HCAEC monolayers. Silencing Wnt5A significantly reduced permeability and improved the barrier function of HCAEC monolayers upon IL-4 treatment. Our study identifies Wnt5A as a novel marker of IL-4 activated vascular endothelium and demonstrates a critical role for Wnt5A in mediating IL-4 induced endothelial barrier dysfunction. Wnt5A could be a potential therapeutic target for reducing microvascular leakage and edema formation in Th2 driven inflammatory diseases.
Skaria et al. (Mon,) conducted a other in Endothelial barrier dysfunction. Interleukin-4 (IL-4) vs. Non-treated cells was evaluated on Endothelial barrier function (transendothelial electrical resistance). IL-4 induces hyperpermeability and impairs the barrier function of human coronary artery endothelial cells by upregulating Wnt5A signaling, which mediates actin cytoskeleton remodeling.