Sustained monocyte activation by persistent challenges with either oxLDL or free cholesterol and underlying mechanisms.

Chronic low-grade inflammation is a hallmark of atherosclerosis and cardiovascular diseases, with monocytes playing a central role in sustaining this pathological state. In this study, we demonstrate that prolonged exposure to oxidized low-density lipoprotein (oxLDL) or cholesterol reprograms murine bone marrow-derived monocytes into a persistent pro-inflammatory phenotype. This is characterized by elevated surface markers (CD49d, CD74, CD38, CD86), enhanced endothelial and T cell interactions, and sustained activation of the Src-SYK-mTORC1-STAT3/5 signaling axis. Notably, the inflammatory state persisted even after stimulus withdrawal, suggesting the establishment of an immune memory-like phenotype. Mechanistically, we defined the membrane clustering of Src is responsible for the generation of intra-cellular stress signaling and sustained monocyte activation, which can be alleviated by the administration of fumagillin, a selective inhibitor of protein myristoylation and Src membrane clustering. Our findings uncover mechanistic insights into the generation of sustained monocyte low-grade inflammatory memory and pinpoint potential therapeutic strategies in erasing low-grade inflammation related to chronic diseases.