The role of non-resolving inflammation in atherosclerosis

Abstract

Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid-derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.

Figure 1. Imbalance of SPMs and leukotrienes (LTs) promotes instability of atherosclerotic plaques.

When the SPM/LT ratio is low (A), resolution of inflammation is impaired, leading to sustained inflammatory Ly6c^hi monocyte influx, platelet aggregation, proinflammatory macrophage polarization, impaired efferocytosis, large necrotic cores, and thin fibrous caps. Conversely, an increase in the SPM/LT ratio (B) promotes resolution, characterized by attenuated Ly6^hi monocyte influx, pro-resolving macrophage polarization, enhanced efferocytosis, decreased necrotic core formation, and thicker fibrous caps.

Figure 2. RvD1 and MerTK signaling promote pro-resolving pathways in macrophages.

Activation of signaling through the FPR2/ALX receptor by RvD1 or through the MerTK receptor by Gas6, protein S, or apoptotic cells (with Gas6 or protein S on the surface of the apoptotic cells) lowers cytoplasmic calcium and thereby decreases the activity of CaMKII. The decrease in CaMKII activity triggers at least two pro-resolving processes. First, it lowers MK2 activity, which increases nonphosphorylated 5-LOX and promotes its nuclear-to-cytoplasmic translocation. In the cytoplasm, 5-LOX mediates the synthesis of SPMs, e.g., LTB₄ in the presence of AA and RvD1 in the presence of DHA, and in the nucleus, 5-LOX causes a concomitant decrease in LT synthesis. The resulting increase in the SPM/LT ratio suppresses plaque progression. Second, suppression of CaMKII activity induces an ATF6-LXRα-MerTK pathway that increases the synthesis of MerTK and thus amplifies the pro-resolving program. Not shown here is that ADAM17-mediated MerTK cleavage, which occurs in advanced lesional macrophages, suppresses both efferocytosis and resolution in macrophages in vitro and in advanced atherosclerotic lesions.