Prosaposin mediates inflammation in atherosclerosis

Mandy M.T. van Leent, Thijs J. Beldman, Yohana C. Toner, Marnix Lameijer, Nils Rother, Siroon Bekkering, Abraham J.P. Teunissen, Xianxiao Zhou, Roy van der Meel, Joost Malkus, Sheqouia A. Nauta, Emma D. Klein, Francois Fay, Brenda L. Sanchez-Gaytan, C. Pérez-Medina, Ewelina Kluza, Yu-Xiang Ye, Gregory Wojtkiewicz, Edward A. Fisher, Filip K. SwirskiMatthias Nahrendorf, Bin Zhang, Yang Li, Bowen Zhang, Leo A.B. Joosten, Gerard Pasterkamp, Arjan Boltjes, Zahi A. Fayad, Esther Lutgens, Mihai G. Netea, Niels P. Riksen, Willem J.M. Mulder, Raphaël Duivenvoorden

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell–specific nanobiologics in apolipoprotein E–deficient (Apoe−/−) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages’ inflammatory activity. By investigating transcriptome modifications, we identified Psap, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that Psap inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of Psap−/− bone marrow to low-density lipoprotein receptor knockout (Ldlr−/−) mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between PSAP expression and inflammation in human carotid atherosclerotic plaques. Our findings provide mechanistic insights into the development of atherosclerosis and identify prosaposin as a potential therapeutic target.
Original languageEnglish
Article numbereabe1433
JournalScience Translational Medicine
Volume13
Issue number584
DOIs
Publication statusPublished - 10 Mar 2021

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