Open AccessProsaposin mediates inflammation in atherosclerosis
Author(s) -
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,
François Fay,
Brenda L. Sánchez-Gaytán,
Carlos Pérez-Medina,
Ewelina Kluza,
Yuxiang Ye,
Gregory R. Wojtkiewicz,
Edward A. Fisher,
Filip K. Świrski,
Matthias Nahrendorf,
Bin Zhang,
Yang Li,
Bowen Zhang,
Leo A. B. Joosten,
Gérard Pasterkamp,
Arjan Boltjes,
Zahi A. Fayad,
Esther Lutgens,
Mihai G. Netea,
Niels P. Riksen,
Willem J. M. Mulder,
Raphaël Duivenvoorden
Publication year - 2021
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.abe1433
Subject(s) - inflammation , pi3k/akt/mtor pathway , p70 s6 kinase 1 , apolipoprotein e , microbiology and biotechnology , biology , signal transduction , cancer research , regulator , immunology , medicine , gene , biochemistry , disease
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.