The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis

Abstract

Accumulating evidence supports the notion that defective phagocytic clearance of dying cells, or defective "efferocytosis," is causally linked to the progression of advanced atherosclerosis. In advanced atherosclerotic lesions, defective efferocytosis leads to post-apoptotic necrosis, expansion of plaque necrotic cores, and susceptibility to atherothrombosis. Both macrophages and DC-like efferocytes are juxtaposed near expanding necrotic cores, where they engage apoptotic cells. In this Viewpoint, we discuss how reduced efferocytosis by macrophages and CD11c(HI) DC-like cells may combine to reduce overall plaque stability and therefore promote susceptibility to acute atherothrombosis.

Figure 1

Possible mechanisms of defective efferocytosis by macrophages in advanced atherosclerosis. Depicted here are several molecules that have been shown to a play a role in macrophage efferocytosis in atherosclerosis. These include the efferocytosis receptors MERTK, αvβ5 integrin, TG2, and LRP (low density lipoprotein related protein). AC receptors can engage bridging molecules such as Gas6/Protein S or MFGE8, which facilitate binding to and phosphatidylserine (PS). There are several hypotheses as to why efferocytosis loses efficiency in advanced plaques, including dysfunction of the molecules as a result of cleavage (MERTK and LRP leading to the soluble isoforms sMER and sLRP respectively), decreased expression (MFGE8), or competitive inhibition by other plaque molecules (sLRP).

Figure 2

Speculation as to how the accumulation of mature DCs in advanced atherosclerosis could promote defective efferocytosis. Although the molecules required for efferocytosis by immature DCs in vivo are not well defined, shown here are several molecules that have been implicated in vitro, namely AXL/TYRO, CD36, and TIM3. These receptors recognize bridging molecules, such as Gas6/Protein S (ProtS) or phosphatidylserine (PS) on ACs. In advanced atheromata, the accumulation of mature DCs (mDCs), which are known to be very poor efferocytes, could contribute to decreased efferocytosis, and thus secondary necrosis.