Identify the initial signaling cascades driving MDM recruitment in early atherosclerosis

Identify the specific molecular signaling cascades that first stimulate recruitment of monocyte-derived macrophages to early atherosclerotic lesions and clarify their dependence on excessive retained low-density lipoprotein in the artery wall, which are currently unknown and assumed in the model via resident-cell inflammatory mediator production proportional to retained LDL lipid density.

Background

In the model, the authors include a source term for inflammatory mediators produced by resident intimal cells (such as smooth muscle cells and tissue-resident macrophages) and link this production to retained LDL lipid. This term drives the recruitment of monocyte-derived macrophages into the lesion.

However, the precise upstream signaling events that initiate this mediator release—and thereby trigger recruitment—are not established. The model therefore adopts a simplifying assumption that resident inflammatory mediator production is proportional to retained LDL, highlighting a mechanistic gap that requires biological clarification to strengthen and validate the modeling framework.