Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation

Abstract

Innate immune cells express danger-associated molecular pattern (DAMP) receptors, T-cell costimulation/coinhibition receptors, and 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-up-regulated DAMP molecules, 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, which are all classic markers of endothelial cell activation, in HAECs. 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 costimulation/coinhibition 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.

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

“…It has been previously reported that shortterm high glucose induces transition of aortic endothelial cells to a long-lived pro-inflammatory status with elevated expression of NF-κB and its downstream pro-atherogenic genes MCP-1 and VCAM-1 both in vitro and in vivo (42), extending the concept of memory training to non-immune endothelial cells. More recently, it was shown that the pro-atherogenic lipid molecule lysophosphatidylcholine (LPC) induces reprogramming of aortic endothelial cells for sustained pro-inflammatory responses (43). Further integrated transcriptomic and epigenetic analysis revealed that LPC induces metabolic and epigenetic changes in activated endothelial cells, including pathways known to be pivotal for the induction of trained immunity (44).…”

An Updated Review of Pro- and Anti-Inflammatory Properties of Plasma Lysophosphatidylcholines in the Vascular System

“…Through their action and production of cytokines they are able to alter the endothelial inflammatory phenotype and contribute to structural instability of atherosclerotic plaques [ 68 , 70 ]. Older studies reported that LPCs may directly contribute to immune cell infiltration during vascular inflammation by increasing the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) [ 71 , 72 ], vascular cell adhesion protein 1 (VCAM-1) [ 73 ] or P-selectin [ 74 ], the expression of damage associated molecular patterns (DAMP) and MHC-II receptors [ 75 ] and by production of chemokines such as monocyte chemoattractant protein (MCP-1), IL-8, and Chemokine (C-C motif) ligand 5 (CCL5), also known as RANTES from endothelial cells. Furthermore, LPC was found to act as a strong chemoattractant for monocytes [ 76 , 77 ], T cells [ 78 ] as well as natural killer (NK) cells [ 79 ], attracting them to sites of inflammation.…”

Proton leak regulates mitochondrial reactive oxygen species generation in endothelial cell activation and inflammation - A novel concept

“…On the other hand, we recognized pathological endothelial cell activation as a mechanism that is triggered by constant exposure of the endothelium to cardiovascular disease risk factor-derived stresses. Continuous bombardment of PAMP and DAMP may trigger prolonged activation of endothelial cells that ultimately lead to recruitment of pathological immune cells to the endothelium leading to development of a continuous inflammatory process that is difficult to resolve [75].…”