Phosphatidylserine enhances anti‐inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways
Abstract
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.
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BibTeX
@article{darabi2026phosphatidylserine,
title = {{Phosphatidylserine enhances anti‐inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways}},
author = {Maryam Darabi and Marie Lhomme and Veronica Dahik and Isabelle Guillas and Eric Frisdal and Emilie Tubeuf and Lucie Poupel and Mili Patel and Emmanuel Gautier and Thierry Huby and Maryse Guerin and Kerry-Anne Rye and Philippe Lesnik and Wilfried Le Goff and Anatol Kontush},
journal = {FASEB Journal},
year = {2026},
month = oct,
doi = {10.1096/fj.201800810r},
url = {https://hal.science/hal-03798360v1},
note = {CC BY-ND 4.0},
}
RIS
TY - JOUR
TI - Phosphatidylserine enhances anti‐inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways
AU - Maryam Darabi
AU - Marie Lhomme
AU - Veronica Dahik
AU - Isabelle Guillas
AU - Eric Frisdal
AU - Emilie Tubeuf
AU - Lucie Poupel
AU - Mili Patel
AU - Emmanuel Gautier
AU - Thierry Huby
AU - Maryse Guerin
AU - Kerry-Anne Rye
AU - Philippe Lesnik
AU - Wilfried Le Goff
AU - Anatol Kontush
PY - 2026
DA - 2026/10/07
JO - FASEB Journal
DO - 10.1096/fj.201800810r
UR - https://hal.science/hal-03798360v1
AB - 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.
SN - 0892-6638
SN - 1530-6860
ER -