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...

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Published in:The FASEB journal Vol. 36; no. 5; p. e22274
Main Authors: Darabi, Maryam, Lhomme, Marie, Dahik, Veronica D, Guillas, Isabelle, Frisdal, Eric, Tubeuf, Emilie, Poupel, Lucie, Patel, Mili, Gautier, Emmanuel L, Huby, Thierry, Guerin, Maryse, Rye, Kerry-Anne, Lesnik, Philippe, Le Goff, Wilfried, Kontush, Anatol
Format: Journal Article
Language:English
Published: United States 01.05.2022
Subjects:
Animals
Anti-Inflammatory Agents - metabolism
Anti-Inflammatory Agents - pharmacology
Lipoproteins, HDL - metabolism
Macrophages - metabolism
Mice
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphatidylserines - metabolism
atherosclerosis
rHDL
phospholipids
inflammation
ISSN:1530-6860, 1530-6860
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Summary: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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ISSN:1530-6860
1530-6860
DOI:10.1096/fj.201800810R