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Phosphatidylserine enhances anti‐inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways

Phosphatidylserine (PS) is a minor phospholipid constituent of high‐density lipoprotein (HDL) that exhibits potent anti‐inflammatory activity. It remains indeterminate whether PS incorporation can enhance anti‐inflammatory effects of reconstituted HDL (rHDL). Human macrophages were treated with rHDL containing phosphatidylcholine alone (PC‐rHDL) or PC and PS (PC/PS‐rHDL). Interleukin (IL)‐6 secretion and expression was more strongly inhibited by PC/PS‐rHDL than PC‐rHDL in both tumor necrosis factor (TNF)‐α‐ and lipopolysaccharide (LPS)‐stimulated macrophages. siRNA experiments revealed that the enhanced anti‐inflammatory effects of PC/PS‐rHDL required scavenger receptor class B type I (SR‐BI). Furthermore, PC/PS‐rHDL induced a greater increase in Akt1/2/3 phosphorylation than PC‐rHDL. In addition, PC/PS but not PC‐rHDL decreased the abundance of plasma membrane lipid rafts and p38 mitogen‐activated protein kinase (p38 MAPK) phosphorylation. Finally, when these rHDL formulations were administered to dyslipidemic low‐density lipoprotein (LDL)‐receptor knockout mice fed a high‐cholesterol diet, circulating IL‐6 levels were significantly reduced only in PC/PS‐rHDL‐treated mice. In parallel, enhanced Akt1/2/3 phosphorylation by PC/PS‐rHDL was observed in the mouse aortic tissue using immunohistochemistry. We concluded that the incorporation of PS into rHDLs enhanced their anti‐inflammatory activity by modulating Akt1/2/3‐ and p38 MAPK‐mediated signaling through SR‐BI in stimulated macrophages. These data identify PS as a potent anti‐inflammatory component capable of enhancing therapeutic potential of rHDL‐based therapy.