Background: In acute or chronic inflammation, the vascular endothelium actively regulates hemostasis as well as immune cell trafficking to enable clearance of infections and cellular damage. Cytokines form the foundation of the communication network that controls the immune system and orchestrates endothelial responses. Although it is generally acknowledged that immune system activation results in the release of a cocktail of cytokines, the current paradigm of vascular inflammation is based on studies using a limited set of individual cytokines, most notably TNFα and IL1β.
Aims: We aim to reveal the distinct cytokine signals that initiate unique adaptive endothelial responses and thereby drive selective immune cell trafficking between blood and tissues by integrating phosphoproteomics, transcriptomics and proteomics.
Methods: Based on ImmuneXpresso datamining a library of recombinant human cytokines was obtained. Blood outgrowth endothelial cells were stimulated with these cytokines for 24 hours and proteomes were determined using quantitative mass spectrometry. Cytokines that displayed distinct endothelial responses were applied as concatenated mixes and sampled for RNAseq and (phospho)proteomic analyses.
Results: To dissect the diversity and selectivity of endothelial inflammation, we studied endothelial responses to a library of 70 cytokines using mass spectrometry based quantitative proteomics. This resulted in the quantification of 4331 proteins of which 261 were statistically significant. These proteomic profiles could be categorized in four main response types. Based on these, we prepared cytokine mixtures to determine their synergistic potential. This revealed that synergistic responses were indeed induced, most notably by the combination of TNFα and IFNγ. Using an expression correlation approach, we highlight a distinct set proteins (e.g. CCL5) that are affected by synergism.
Conclusions: Taken together, we provide a comprehensive map of the endothelial-cytokine interactions that may pave the way for rational design of therapeutic strategies aimed to selectively modulate immune cell trafficking across the vessel wall.
To cite this abstract in AMA style:Hoogendijk AJ, Janssen EFJ, van den Eshof BL, van Alphen FPJ, van der Zwaan C, Meijer AB, van den Biggelaar M. Cytokine Network Architecture at the Endothelial Interface [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/cytokine-network-architecture-at-the-endothelial-interface/. Accessed November 26, 2020.
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