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 (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.

Monocytes and macrophages as nanomedicinal targets for improved diagnosis and treatment of disease.

The important role of monocytes and macrophages in diseases like cancer and atherosclerosis has started to get uncovered in the last decade. In addition, subsets of these cell types are believed to participate in the initiation and aggravation of several diseases including cancer and cardiovascular disease. For this reason, monocytes and macrophages have recently been identified as interesting targets for both diagnosis and treatment of the aforementioned pathologies. Compared with free therapeutic or imaging agents, nanoparticle formulations provide several advantages that improve the pharmacokinetics and bioavailability of these agents. In addition, the possibility of surface functionalization creates numerous ways to optimize nanoparticle delivery. Recent advances in nanomedicine have led to the development of multifunctional nanoparticles that allow simultaneous diagnosis and treatment of monocytes and macrophages with high specificity. Relying on the inherent ability of monocytes and macrophages to easily take up foreign particles, the use of nanoparticles provides a precious opportunity for the management of several inflammatory diseases.