OxLDL-mediated immunologic memory in endothelial cells.

Area of Science:

• Immunology
• Cell Biology
• Metabolic Regulation

Background:

• Trained innate immunity involves metabolic reprogramming and sustained activation of immune cells.
• Oxidized low-density lipoprotein (oxLDL) is implicated in inflammatory processes.
• Endothelial cells play a crucial role in vascular health and inflammation.

Purpose of the Study:

• To investigate if trained innate immunity mechanisms regulate endothelial cell activation by oxLDL.
• To explore the metabolic and epigenetic reprogramming in endothelial cells following oxLDL priming.
• To assess the functional consequences of oxLDL-induced endothelial cell memory on immune cell interactions.

Main Methods:

• Human aortic endothelial cells (HAECs) were primed with oxLDL and restimulated with a TLR2 agonist.
• Analysis of cytokine production, metabolic changes (glucose consumption, lactate production), and epigenetic modifications.
• Inhibition of key signaling pathways (mTOR-HIF1α) and histone methyltransferases.
• Live cell imaging to assess monocyte adhesion and transmigration.

Main Results:

• OxLDL priming induced a proinflammatory memory in HAECs, with increased cytokine production upon restimulation.
• This memory was TLR2-dependent and associated with metabolic reprogramming (mTOR-HIF1α activation) and epigenetic changes.
• Inhibition of mTOR-HIF1α or histone methyltransferases blocked the trained immunity phenotype.
• Primed HAECs exhibited increased ICAM-1 expression and enhanced monocyte adhesion and transmigration.

Conclusions:

• OxLDL-mediated endothelial cell activation is an immunologic event triggering metabolic and epigenetic reprogramming.
• Mechanisms of trained innate immunity in immune cells also govern sustained proinflammatory responses in endothelial cells.
• This oxLDL-induced endothelial cell memory enhances atheroprone functions, potentially contributing to atherosclerosis.