7/31/2023 0 Comments React cytoscapeCombining multiple omics levels, we dissected the molecular basis of these inflammatory states from signaling (phosphoproteome) to mRNA transcription (transcriptome), protein regulation (proteome) and protein secretion (secretome). Moreover, combined stimulation of TNFα and IFNγ resulted in a synergetic EC response. However, upon stimulation with an unbiased cytokine library, we observed predominantly unique inflammatory states for TNFα and IFNγ. We show that ECs express the receptor-repertoire to facilitate various cytokine signals. Therefore, in this study, we set out to dissect the molecular signatures of endothelial-cytokine responses, employing blood outgrowth endothelial cells (BOECs), also known as endothelial colony forming cells, as our source of ECs because of their extensive, robust expansion, expression of mature vascular EC markers and ability to be isolated from adult donors 24, 25. Although underlying mechanisms have been proposed, a system-wide EC response has not been characterized. Moreover, synergism between cytokines such as TNFα and interferon-gamma (IFNy) has been observed in ECs and linked to detrimental effects in inflammatory disorders 20, 21, 22, 23. This endothelial dysfunction is implicated in several multi-facetted inflammatory diseases, including transfusion related acute lung injury, sepsis, rheumatoid arthritis, acute respiratory distress syndrome (ARDS), eye vasculopathies, chronic kidney disease and COVID-19 10, 11, 12, 13, 14, 15, 16, 17, 18, 19.Īlthough both endothelial homeostasis and cytokines are deregulated in these diseases, the molecular basis which orchestrates adaptive endothelial-cytokine interactions is mostly confined to research on tumor necrosis factor-alpha (TNFα). However, although ECs carry these immune-modulating properties and are among the first cells to come into contact with pathogens, they are rarely mentioned in immune cell networks 7, 8, 9.ĭeregulation of EC homeostasis can result in over-inflammatory or hyper-coagulation states of the endothelium. In addition to the transmigration of immune cells, ECs have several immunomodulatory capacities such as antigen presentation and cytokine secretion 5, 6. For their role in this adaptive synapse, ECs are well-equipped to sense environmental cues, such as mechanical stress, hormones (e.g., vasopressin, histamine), cells (e.g., neutrophils, monocytes, platelets) and other external stimuli (e.g., thrombin, cytokines) 2, 3, 4, 5. Moreover, ECs are crucial gatekeepers controlling the trafficking of immune cells into and out of tissues during inflammation. Apart from facilitating oxygen, nutrient, and waste product exchange, ECs control hemostasis by attracting platelets to seal breaches in the vascular walls during primary hemostasis 1. This 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.Įndothelial cells (ECs) line the inside of our blood vessels and form a dynamic interface between blood and surrounding tissues. Synergy resulted in cooperative activation of transcript induction. We employed a multi-omics approach to dissect these inflammatory states, combining (phospho-) proteome, transcriptome and secretome and found, depending on the stimulus, a wide-array of altered immune-modulating processes, including complement proteins, MHC complexes and distinct secretory cytokines. Notably, combined TNFα + IFNγ stimulation induced an additional synergetic inflammatory signature. Applying an unbiased cytokine library, we determined that TNFα and IFNγ induced the largest EC response resulting in distinct proteomic inflammatory signatures. Here, we aim to dissect the system-wide molecular mechanisms of inflammatory endothelial-cytokine responses. Vascular endothelial cells (ECs) form a dynamic interface between blood and tissue and play a crucial role in the progression of vascular inflammation.
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