Mertk Receptor Mutation Reduces Efferocytosis Efficiency and Promotes Apoptotic Cell Accumulation and Plaque Necrosis in Atherosclerotic Lesions of Apoe ^−/− Mice

Abstract

Objective-Atherosclerotic plaques that are prone to disruption and acute thrombotic vascular events are characterized by large necrotic cores. Necrotic cores result from the combination of macrophage apoptosis and defective phagocytic clearance (efferocytosis) of these apoptotic cells. We previously showed that macrophages with tyrosine kinase- Key Words: atherosclerosis-pathophysiology Ⅲ apoptosis Ⅲ phagocytosis Ⅲ animal models of human disease P revention and regression of human atherothrombotic vascular disease requires an understanding of the underlying mechanisms that promote advanced plaque progression. Acute coronary artery syndromes are often associated with the presence of so-called vulnerable plaques. These plaques are characterized by focal thinning of the fibrous cap, a high level of inflammatory cytokines and matrix proteases, apoptosis of intimal cells, and expansion of a lipid-laden necrotic core.

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

“…29,30 Moreover, functional mutations of the GAS-6 receptor, Mer, [34][35][36][37] resulted in reduced phagocytosis and accumulation of apoptotic cells in the plaque. 36,37 Although speculative, these data raise a possibility that elevated GAS-6 expression, 29,30 might contribute to opsonization of PSox-expressing apoptotic cells, thereby priming them for Mer receptordependent phagocytosis versus engagement by other receptors. On the other hand, lower GAS-6 expression and/or higher expression of MFG-E8/alphav-beta5 might shift the receptor preference, and hence post-phagocytic signaling towards anti-inflammatory pathways.…”

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

“…Treatment with RMT1‐10 reduced apoptotic cell numbers in lesions by 30% ( P <0.05; Figure 5C). As apoptotic cell numbers are related to the size of the necrotic core,35 we next assessed necrotic core size. Necrotic core in lesions of RMT1‐10‐treated mice were reduced by nearly 50% ( P <0.05; Figure 5D).…”

Diabetes mellitus and apoptosis: inflammatory cells

“…Furthermore, activation of macrophage receptors, apart from those mentioned as part of the extrinsic apoptotic pathway, have been shown to promote macrophage apoptosis in models of atherosclerosis. These receptors include: LDL receptor-1 (LOX-1) [122], SR-A, CD36 [123], toll-like receptors (TLRs) [124,125], canabinoid 2 (CB2) receptor [126], Mertk [127], prostaglandin receptor EP-4 [128], TNFR [129], interleukin-1 receptor-associated kinase (IRAK) [130], and phospholipase C (PLC)-b [131].…”

“…Ox-LDL has also been shown to inhibit efferocytosis whilst encouraging lipid uptake, in a process that involves TLR activation [143]. Other receptors implicated in macrophage efferocytosis in atherosclerosis include: Mertk [127,144], apolipoprotein E (APOe), Fas, transglutaminase-2, complement protein C1q and lactadherin [145].…”