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Li X , Wang L , Fang P , Sun Y , Jiang X , Wang H , Yang XF
Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation
J Biol Chem. 2018 Jul 13;293(28) :11033-11045
PMID: 29769317    PMCID: PMC6052225    URL: https://www.ncbi.nlm.nih.gov/pubmed/29769317
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Abstract
Innate immune cells express danger-associated molecular pattern (DAMP) receptors, T-cell co-stimulation/co-inhibition receptors, and the major histocompatibility complex II (MHC-II). We have recently proposed that endothelial cells can serve as innate immune cells, but the molecular mechanisms involved still await discovery. Here, we investigated whether human aortic endothelial cells (HAECs) could be transdifferentiated into innate immune cells by exposing them to hyperlipidemia-upregulated DAMP molecules, i.e. lysophospholipids. Performing RNA-Seq analysis of lysophospholipid-treated HAECs, we found that lysophosphatidylcholine (LPC) and lysophosphatidylinositol (LPI) regulate largely distinct gene programs, as revealed by principal component analysis. Metabolically, LPC up-regulated genes that are involved in cholesterol biosynthesis, presumably through sterol regulatory element-binding protein 2 (SREBP2). By contrast, LPI up-regulated gene transcripts critical for the metabolism of glucose, lipids, and amino acids. Of note, we found that LPC and LPI both induce adhesion molecules, cytokines, and chemokines in HAECs, which are all classic markers of endothelial cell activation. Moreover, LPC and LPI shared the ability to transdifferentiate HAECs into innate immune cells, including induction of potent DAMP receptors, such as CD36 molecule, T-cell co-stimulation/co-inhibition receptors, and MHC-II proteins. The induction of these innate-immunity signatures by lysophospholipids correlated with their ability to induce up-regulation of cytosolic calcium and mitochondrial reactive oxygen species. In conclusion, lysophospholipids such as LPC and LPI induce innate immune cell transdifferentiation in HAECs. The concept of prolonged endothelial activation, discovered here, is relevant for designing new strategies for managing cardiovascular diseases.
Notes
1083-351x Li, Xinyuan Wang, Luqiao Fang, Pu Sun, Yu Jiang, Xiaohua Wang, Hong Yang, Xiao-Feng Journal Article United States J Biol Chem. 2018 May 16. pii: RA118.002752. doi: 10.1074/jbc.RA118.002752.