Defective Mer Receptor Tyrosine Kinase Signaling in Bone Marrow Cells Promotes Apoptotic Cell Accumulation and Accelerates Atherosclerosis

Inserm U689, Hôpital Lariboisière, 41, Bd de la Chapelle, 75010 Paris, France.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 06/2008; 28(8):1429-31. DOI: 10.1161/ATVBAHA.108.169078
Source: PubMed


To study the role of Mer receptor tyrosine kinase (mertk) in atherosclerosis.
We irradiated and reconstituted atherosclerosis-susceptible C57Bl/6 low-density lipoprotein receptor-deficient female mice (ldlr(-/-)) with either a mertk(+/+) or mertk(-/-) (tyrosine kinase-defective mertk) bone marrow. The mice were put on high-fat diet for either 8 or 15 weeks. Mertk deficiency led to increased accumulation of apoptotic cells within the lesions, promoted a proinflammatory immune response, and accelerated lesion development.
Mertk expression by bone marrow-derived cells is required for the disposal of apoptotic cells and controls lesion development and inflammation.

Download full-text


Available from: Kiyoka Kinugawa,
  • Source
    • "This counterbalance comes through the alteration or down regulation of ‘don’t eat me’ signals, expressed on viable cells. These include CD300a,68 CD3169 and CD47,45 which all vary in mechanism of function. CD300a is newly identified as an inhibitor of AC engulfment via competitive phospholipid binding on apoptotic cells.99,101 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called ‘eat me’ and ‘don’t eat me’ signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies.
    Journal of Cell Death 10/2013; 6(1-3932-JCD-Current-Understanding-of-the-Mechanisms-for-Clearance-of-Apoptotic-Cel.pdf):57-68. DOI:10.4137/JCD.S11037
  • Source
    • "Hypocomplementemia has been linked to defective clearance of apoptotic cells (9), which is considered to be a key pathogenetic mechanism in the development of both lupus and atherosclerosis (4). Acceleration of murine atherosclerosis attributed to accumulation of apoptotic cells within atherosclerotic lesions has been described in the context of deficiency of complement C1q (10), Mer receptor tyrosine kinase (11, 12), and lactadherin (13). A lupus-like phenotype associated with defective uptake of apoptotic cells has also been demonstrated in these mice (9, 14, 15). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the accelerating effect of systemic lupus erythematosus (SLE) on atherosclerosis is well established, the underlying mechanisms are unknown. The aim of this study was to explore the hypothesis that lupus autoimmunity modulates the effect of hypercholesterolemia in driving arterial pathologic development. Low-density lipoprotein receptor-deficient (Ldlr(-/-) ) mice were crossed with B6.129-Sle16 (Sle16)-congenic autoimmune mice to obtain Sle16. Ldlr(-/-) mice, which were compared with Ldlr(-/-) and Sle16 control mice. All mice were fed either a low-fat or high-fat diet. Groups of mice were compared, by strain and by diet group, for features of accelerated atherosclerosis and autoimmunity. Presence of the Sle16 locus significantly increased the extent of atherosclerosis in Ldlr(-/-) mice. Circulating C3 levels were significantly reduced in Sle16.Ldlr(-/-) mice compared to Ldlr(-/-) control mice and this was paralleled by a marked reduction in arterial lesion C3 deposition despite similar levels of IgG deposition between the groups. Increased numbers of apoptotic cells in plaques were observed in the high-fat-fed Sle16.Ldlr(-/-) mice, consistent with the observed defective clearance of cellular debris. After receiving the high-fat diet, Sle16.Ldlr(-/-) mice developed glomerulonephritis and displayed enhanced glomerular C3 deposition. These results indicate that accelerated atherosclerosis and renal inflammation in SLE are closely linked via immune complex formation and systemic complement depletion. However, whereas hyperlipidemia will enhance renal immune complex-mediated complement activation and the development of nephritis, accelerated atherosclerosis is, instead, related to complement depletion and a reduction in the uptake of apoptotic/necrotic debris. These results suggest that aggressive treatment of hyperlipidemia in patients with SLE may reduce the occurrence of lupus nephritis, as well as diminish the risk of accelerated atherosclerosis.
    Arthritis & Rheumatology 08/2012; 64(8):2707-18. DOI:10.1002/art.34451 · 7.76 Impact Factor
  • Source
    • "Another important efferocytosis receptor in atherosclerosis in MERTK. Mice deficient in the tyrosine kinase MER (MERTK), have a defect in macrophage efferocytosis and this correlated with an increase in plaque inflammation and plaque necrosis (Ait-Oufella et al., 2008; Thorp et al., 2008). MERTK is involved in both efferocytosis and in anti-inflammatory responses (Camenisch et al., 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In cardiovascular disorders including advanced atherosclerosis and myocardial infarction (MI), increased cell death and tissue destabilization is associated with recruitment of inflammatory monocyte subsets that give rise to differentiated macrophages. These phagocytic cells clear necrotic and apoptotic bodies and promote inflammation resolution and tissue remodeling. The capacity of macrophages for phagocytosis of apoptotic cells (efferocytosis), clearance of necrotic cell debris, and repair of damaged tissue are challenged and modulated by local cell stressors that include increased protease activity, oxidative stress, and hypoxia. The effectiveness, or lack thereof, of phagocyte-mediated clearance, in turn is linked to active inflammation resolution signaling pathways, susceptibility to atherothrombosis and potentially, adverse post MI cardiac remodeling leading to heart failure. Previous reports indicate that in advanced atherosclerosis, defective efferocytosis is associated with atherosclerotic plaque destabilization. Post MI, the role of phagocytes and clearance in the heart is less appreciated. Herein we contrast the roles of efferocytosis in atherosclerosis and post MI and focus on how targeted modulation of clearance and accompanying resolution and reparative signaling may be a strategy to prevent heart failure post MI.
    Frontiers in Immunology 03/2012; 3:39. DOI:10.3389/fimmu.2012.00039
Show more