HDL-associated phosphatidylserine blunts myeloid activation and protects from atherosclerosis
Year: 2025
Type: preprint
Abstract: ABSTRACT Background and aims Lipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, in vitro assays and in vivo experiments in Apoe -/- mice. Methods Human lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In vitro assays were carried out using human monocytes and macrophages, and in vivo experiments included histopathological, immunophenotyping and single-cell transcriptomic analyses. Results In humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. In vitro , this formulation potently inhibited inflammatory cytokine production on human myeloid cells. Our in-depth in vivo experiments provided evidence of the formulation’s potent plaque-stabilizing and anti-inflammatory actions. These effects were mediated by a shift in the monocyte/macrophage compartment toward homeostatic/repairing phenotypes. Conclusions Collectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies.
Authors: Aurora Bernal, Arslan Hamid, Cristina Grao-Roldán, Alice Scarpa, Iria Sánchez, José Ángel Nicolás-Ávila, Laura Pena-Couso, Mohamed H. Yaghmour, Alberto Benguría, Aránzazu Rosado, Lucía Sánchez-García, Carlos Torroja, Ana Dopazo, Fátima Sánchez-Cabo, Andrés Hidalgo, Max L. Senders, Mandy M.T. van Leent, Lea Seep, Jan Hasenauer, Katarzyna Placek, Christoph Thiele, Mihai G. Netea, Willem J.M. Mulder, Niels P. Riksen, Carlos Pérez-Medina
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades, Dutch Cardiovascular Alliance, Deutsche Forschungsgemeinschaft, Centro Nacional de Investigaciones Cardiovasculares, National Institutes of Health, Instituto de Salud Carlos III, Agencia Estatal de Investigación, National Heart, Lung, and Blood Institute
Awards: G1602493886, SFB 1454: Metaflammation und Zelluläre Programmierung, G1959237123, G2152959462, G2262748287, G288011245, G3480869486, G425668148, G4549622993, G7084143925, G7191602444, G7863371703, G8497050386, EXC 2151: ImmunoSensation2 the immune sensory system, Stress-induced immune reprogramming in cardiovascular disease, G926782147
OpenAlex ID: W4416837929