Prosaposin mediates inflammation in atherosclerosis.

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 (<i>Apoe</i> ^-/-) 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 <i>Psap</i>, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that <i>Psap</i> inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of <i>Psap</i> ^-/- bone marrow to low-density lipoprotein receptor knockout (<i>Ldlr</i> ^-/-) mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between <i>PSAP</i> 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.