Cytokine Circuits in Cardiovascular Disease

Abstract

Arterial inflammation is a hallmark of atherosclerosis, and appropriate management of this inflammation represents a major unmet therapeutic need for cardiovascular disease patients. Here, we review the diverse contributions of immune cells to atherosclerosis, the mechanisms of immune cell activation in this context, and the cytokine circuits that underlie disease progression. We discuss the recent application of these insights in the form of immunotherapy to treat cardiovascular disease and highlight how studies on the cardiovascular co-morbidity that arises in autoimmunity might reveal additional roles for cytokines in atherosclerosis. Currently, data point to interleukin-1β (IL-1β), tumor necrosis factor (TNF), and IL-17 as cytokines that, at least in some settings, are effective targets to reduce cardiovascular disease progression.

Figure 1.. A close look at the cellular composition of atherosclerotic plaques and their connection to cytokine circuits

Like a mysterious crime thriller, the complex interactions of cells and cytokines within the atherosclerotic plaque promoting dysfunction are still being recognized. This figure schematizes an atherosclerotic plaque within a magnifying glass. The various cell types in the plaque are delineated around the outer margins. Cytokine circuits that promote adverse pathology are shown in red text, favorable pathways in green text, and neutral pathways in black.

Figure 2.. Monocyte – macrophage differentiation pathways in atherosclerotic disease

The diversity of myeloid cells within atherosclerotic plaque was recently studied by single-cell RNA-sequencing. Furthermore, literature in other organ systems, as discussed in the text, highlights evidence that intermediate stages of monocytes differentiating to tissue resident macrophages pass through a transient pro-inflammatory phase. However, inflammatory and less inflammatory resident states may be distinct pathways. On the right, we depict a predicted cell fate map based on Monocle analysis of the work by Kim et al. (Kim et al., 2018)

Figure 3.. Systemic modifiers of atherosclerosis

A few of the systemic modifiers of atherosclerosis are depicted here and discussed in the text. Text in red depict adverse signals that worsen cardiovascular disease and text in blue depict mechanisms that suppress cardiovascular disease, although recent studies have not found a benefit for vitamin D, as once thought.

Figure 4.. Inflammasome activation in atherosclerosis progression

The two-step signaling sequence in activation of the inflammasome is schematized here and discussed in the text. We emphasize the concept that, in atherosclerosis, cholesterol crystals may be the disease-driving signal that links cholesterol and inflammatory pathways in atherosclerosis.