Atherosclerosis is a chronic disease driven by both dysregulated lipid metabolism and sustained inflammation. Traditional murine models of atherosclerosis rely on genetic mutations affecting lipid metabolism, such as in ApoE or LDLR, which limits the ability to study immune-specific contributions independent of lipid disturbance. As a result, models that isolate and investigate inflammation-driven mechanisms of atherosclerosis have remained largely unavailable.
To address this, we developed a novel in vivo model of predominantly immune-triggered atherosclerosis. Using transgenic CD11c.DTR-GFP mice—which express the diphtheria toxin receptor (DTR) under the control of the CD11c promoter—we generated bone marrow chimeras by transplanting their hematopoietic cells into wild-type C57BL/6 recipients. This approach enabled long-term, selective depletion of CD11c⁺ antigen-presenting cells (APCs) via diphtheria toxin administration, without interfering with lipid metabolism pathways.
Remarkably, mice with sustained CD11c⁺ cell depletion developed significantly larger atherosclerotic plaques compared to undepleted controls. This was accompanied by pronounced alterations in the immune cell composition within the aortic wall, including a reduction in tolerogenic dendritic cells (DCs), a skewing toward pro-inflammatory Ly6G⁺/Ly6C⁺ monocytes, and shifts in T cell populations. Systemically, we observed increased inflammatory responses in lymphoid organs and peripheral blood, marked by elevated levels of TNF-α, IFNγ, IL-17, and IL-1β.
This model offers a unique tool to dissect the immune-specific drivers of atherosclerosis independent of lipid dysregulation and highlights the critical role of CD11c⁺ cells in maintaining vascular immune homeostasis
