A Novel Biological Role for von Willebrand Factor in Linking Primary Hemostasis and Innate Immunity

The plasma multimeric glycoprotein von Willebrand factor (VWF) plays a critical role in primary hemostasis by tethering platelets to exposed collagen at sites of vascular injury. Recent studies have identified additional biological roles for VWF, and in particular suggest that VWF may play an important role in regulating inflammatory responses. Critically however, the molecular mechanisms through which VWF exerts its immuno-modulatory effects remains poorly understood. In this study, we report for the first time that VWF binding to macrophages triggers direct downstream MAPkinase signaling leading to NF-kB activation and production of pro-inflammatory cytokines and chemokines. In keeping with these observations, VWF binding also promotes macrophage M1 polarization and shifts macrophage metabolism towards glycolysis in a p38 dependent manner. Cumulatively, our findings define an entirely new biological role for VWF in modulating macrophage function, and thereby establish a novel link between primary hemostasis and innate immunity. Comparative gene expression profiling analysis of RNA-seq data on BMDMs after incubation in the presence of pd-VWF, LPS or PBS control for 3.5 hours or 16 hours.