Mechanisms and consequences of efferocytosis in advanced atherosclerosis

Abstract

Throughout atherosclerotic lesion development, intimal macrophages undergo apoptosis, a form of death that usually prevents cellular necrosis. In advanced atherosclerotic lesions, however, these apoptotic macrophages become secondarily necrotic and coalesce over time into a key feature of vulnerable plaques, the necrotic core. This event is critically important, as necrotic core formation in these advanced atheromata is thought to promote plaque disruption and ultimately, acute atherothrombotic vascular disease. Increasing evidence suggests that the mechanism behind postapoptotic macrophage necrosis in advanced atherosclerosis is defective phagocytic clearance or "efferocytosis" of the apoptotic cells. Thus, understanding the cellular and molecular mechanisms of efferocytosis in atherosclerosis and why efferocytosis becomes defective in advanced lesions is an important goal. Molecular-genetic causation studies in mouse models of advanced atherosclerosis have provided evidence that several molecules known to be involved in efferocytosis, including TG2, MFG-E8, complement C1q, Mertk, lysoPC, and Fas, play important roles in the clearance of apoptotic cells in advanced plaques. These and future insights into the molecular mechanisms of defective efferocytosis in advanced atheromata may open the way for novel therapeutic strategies for atherothrombotic vascular disease, the leading cause of death in the industrialized world.

Figure 1.

Cross-section of an advanced human coronary plaque showing a large necrotic core, plaque rupture, and lumenal thrombosis. Mφs, Macrophages.

Figure 2.

Efferocytosis of apoptotic macrophages and how it may go awry in advanced atheroma. (A) Physiologic efferocytosis can involve many molecules, including a diverse array of receptors, ligands, and bridging molecules. An increase in the ratio of so-called find-me:don’t-eat-me signals also enables efferocytosis. Depicted here are several molecules that have been shown to a play a role in murine models of atherosclerosis. Successful recognition and engulfment of apoptotic bodies lead to avoidance of cellular necrosis and anti-inflammatory signaling. CRT, Calreticulin. (B) In advanced atheromata, there is evidence that efferocytosis becomes less effective, leading to secondary macrophage necrosis and inflammation, two processes that likely promote plaque vulnerability. There are several hypotheses as to why efferocytosis loses efficiency in advanced plaques, including dysfunction of the molecules depicted in A as a result of cleavage, decreased expression, or competitive inhibition of binding by other plaque molecules. See text for details.