The LOX-1 scavenger receptor plays a central role in multiple positive feedback loops driving the escalation of oxLDL uptake by macrophages.

Foam cells derived from macrophages and smooth muscle cells are formed by the uncontrolled uptake of modified low-density lipoprotein (LDL) and are the main cellular components of atherosclerotic lesions. Uptake of oxidized LDL (oxLDL) by macrophages occurs via receptor-mediated endocytosis through various scavenger receptors. Although resting macrophages internalize modified LDL mainly via SR-A and CD36 receptors, evidence suggests an important role for LOX-1 in the transformation of macrophages into foam cells, despite the low level of LOX-1 on the surface membrane of resting macrophages. Here we describe novel positive feedback loops involving anaphylatoxin C3a and its receptor, which lead to increased LOX-1 levels in macrophages and reveal the molecular mechanisms underlying these processes. Impact statement Little is known about processes which control the transformation of macrophages into foam cells in atherosclerotic lesions. Here, we describe novel positive feedback loops associated with anaphylatoxin C3a and its receptor, which lead to escalation of oxLDL uptake by macrophages, and reveal the central role of the LOX-1 receptor in this process.