Macrophage migration inhibitory factor induces vascular leakage via autophagy

Abstract

ABSTRACT Vascular leakage is an important feature of acute inflammatory shock, which currently has no effective treatment. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that can induce vascular leakage and plays an important role in the pathogenesis of shock. However, the mechanism of MIF-induced vascular leakage is still unclear. In this study, using recombinant MIF (rMIF), we demonstrated that MIF induced disorganization and degradation of junction proteins and increased the permeability of human endothelial cells in vitro. Western blotting analysis showed that rMIF treatment induced LC3 conversion and p62 degradation. Inhibition of autophagy with a PI3K inhibitor (3-MA), a ROS scavenger (NAC) or autophagosomal-lysosomal fusion inhibitors (bafilomycin A1 and chloroquine) rescued rMIF-induced vascular leakage, suggesting that autophagy mediates MIF-induced vascular leakage. The potential involvement of other signaling pathways was also studied using different inhibitors, and the results suggested that MIF-induced vascular leakage may occur through the ERK pathway. In conclusion, we showed that MIF triggered autophagic degradation of endothelial cells, resulting in vascular leakage. Inhibition of MIF-induced autophagy may provide therapeutic targets against vascular leakage in inflammatory shock.