The endothelial inflammatory repertoire: a multi-omic delineation of cytokine induced endothelial inflammatory states

Vascular endothelial cells (ECs) form a dynamic interface between blood and tissue and play a crucial role in the progression of vascular inflammation. Here, we explored the underlying molecular mechanisms of endothelial-cytokine responses which govern inflammation. Applying an unbiased cytokine library, we determined TNFα and IFNγ induced the largest EC response and had distinct proteomic inflammatory signatures. Moreover, combined TNFα + IFNγ stimulation induced a third synergetic inflammatory state. We employed a multi-omics approach combining (phospho-) proteome, transcriptome and secretome to delineate these inflammatory states and found that endothelial cells contain a wide-array of immune-modulating capacities such as complement proteins, MHCI and MHCII complexes and distinct secretory cytokine production per stimulus. Synergy was regulated through cooperative interplay of transcript induction. This extensive resource describes the intricate molecular mechanisms that are at the basis of endothelial inflammation and supports the adaptive immunomodulatory role of the endothelium in host defense and vascular inflammation.