Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression

Abstract

Atherosclerosis, the underlying cause of coronary artery (CAD) and other cardiovascular diseases, is initiated by macrophage-mediated immune responses to lipoprotein and cholesterol accumulation in artery walls, which result in the formation of plaques. Unlike at other sites of inflammation, the immune response becomes maladaptive and inflammation fails to resolve. The most common treatment for reducing the risk from atherosclerosis is low density lipoprotein cholesterol (LDL-C) lowering. Studies have shown, however, that while significant lowering of LDL-C reduces the risk of heart attacks to some degree, there is still residual risk for the majority of the population. We and others have observed "residual inflammatory risk" of atherosclerosis after plasma cholesterol lowering in pre-clinical studies, and that this phenomenon is clinically relevant has been dramatically reinforced by the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial. This review will summarize the role of the innate immune system, specifically macrophages, in atherosclerosis progression and regression, as well as the pre-clinical and clinical models that have provided significant insights into molecular pathways involved in the resolution of plaque inflammation and plaque regression. Partnered with clinical studies that can be envisioned in the post-CANTOS period, including progress in developing targeted plaque therapies, we expect that pre-clinical studies advancing on the path summarized in this review, already revealing key mechanisms, will continue to be essential contributors to achieve the goals of dampening plaque inflammation and inducing its resolution in order to maximize the therapeutic benefits of conventional risk factor modifications, such as LDL-C lowering.

Keywords: atherosclerosis progression; atherosclerosis regression; clinical trials as topic; innate immunity; macrophages; pre-clinical models.

Figure 1

Representative Murine Plaque Regression Models. Selected models taken from those described in the text: (A) Transplant Model, (B) Reversa Model,and (C) PCSK9 model. For each model: (i) Schematic of experiment, (ii) Quantification of CD68⁺ (macrophage) area, *<0.05, (iii) representative CD68⁺ stained immunohistochemical sections, and (iv) original reference from which the images are modified from. Despite different methods to drastically lower circulating lipids,all of these models show a significant (*<0.05) reduction in CD68⁺ macrophage content in regression groups compared to respective baseline and/or progression groups.

Figure 2

Key molecules involved in innate immunity and atherosclerosis pathogenesis. There are multiple molecules and pathways involved in the progression of atherosclerosis that have also been implicated in atherosclerosis regression. They include: 1. LDL/oxLDL, 2. Chemokines that induce monocyte recruitment into the plaque, 3. HDL, 4. Proliferation, 5. Polarization, 6. Pro-inflammatory mediators, 7. Pro-resolving mediators, 8. Apoptosis and efferocytosis, and 9. Macrophage egress out of the plaque.