IL-1β disrupts blood-brain barrier development by inhibiting endothelial Wnt/β-catenin signaling

Abstract

During neuroinflammation, the proinflammatory cytokine Interleukin-1{beta} (IL-1{beta}) impacts blood-brain barrier (BBB) function by disrupting brain endothelial tight junctions, promoting vascular permeability, and increasing transmigration of immune cells. Here, we examined the effects of Il-1{beta} on the in vivo development of the BBB. We generated a doxycycline-inducible transgenic zebrafish model that drives secretion of Il-1{beta} in the CNS. To validate the utility of our model, we showed Il-1{beta} dose-dependent mortality, recruitment of neutrophils, and expansion of microglia. Using live imaging, we discovered that Il-1{beta} causes a significant reduction in CNS angiogenesis and barriergenesis. To demonstrate specificity, we rescued the Il-1{beta} induced phenotypes by targeting the zebrafish il1r1 gene using CRISPR/Cas9. Mechanistically, we determined that Il-1{beta} disrupts BBB development by decreasing Wnt/{beta}-catenin transcriptional activation in brain endothelial cells. Given that several neurodevelopmental disorders are associated with inflammation, our findings support further investigation into the connections between proinflammatory cytokines, neuroinflammation, and neurovascular development.