Department of Molecular Hematology, Sanquin Research, Amsterdam, 1066 CX, The Netherlands.
Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, 3584 CS, The Netherlands.
Commun Biol. 2023 May 15;6(1):525. doi: 10.1038/s42003-023-04897-w.
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 aim to dissect the system-wide molecular mechanisms of inflammatory endothelial-cytokine responses. Applying an unbiased cytokine library, we determined that TNFα and IFNγ induced the largest EC response resulting in distinct proteomic inflammatory signatures. Notably, combined TNFα + IFNγ stimulation induced an additional synergetic inflammatory signature. 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. Synergy resulted in cooperative activation of transcript induction. 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.
血管内皮细胞 (ECs) 形成了血液和组织之间的动态界面，在血管炎症的发展中起着至关重要的作用。在这里，我们旨在剖析炎症性内皮细胞-细胞因子反应的系统范围的分子机制。应用无偏细胞因子文库，我们确定 TNFα 和 IFNγ 诱导了最大的 EC 反应，导致了独特的蛋白质组学炎症特征。值得注意的是，联合 TNFα+IFNγ 刺激诱导了额外的协同炎症特征。我们采用多组学方法剖析这些炎症状态，结合（磷酸化）蛋白质组、转录组和分泌组，发现根据刺激的不同，广泛存在改变的免疫调节过程，包括补体蛋白、MHC 复合物和独特的分泌细胞因子。协同作用导致转录诱导的协同激活。本资源描述了内皮炎症基础上的复杂分子机制，并支持内皮在宿主防御和血管炎症中的适应性免疫调节作用。
