Article

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: 6.34). 06/2008; 28(8):1429-31. DOI: 10.1161/ATVBAHA.108.169078
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
112 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Syndecan-1 (Sdc-1) is a member of a family of cell surface proteoglycans, which has been reported to participate in the regulation of events relevant to tissue repair and chronic injury responses, including cell-substrate interactions, matrix remodeling, and cell migration. In this study, we report the functional significance of Sdc-1 in polarized macrophage populations and its role in adhesion and motility events relevant to resolution of the inflammatory program. Macrophage Sdc-1 expression is associated with differentiated M2 macrophages with high intrinsic motility, and Sdc-1 deficiency is characterized by impaired migration and enhanced adhesion. Leukocyte infiltration and emigration were examined in a thioglycollate-induced model of peritonitis in Sdc-1(+/+) and Sdc-1(-/-) mice. Although the infiltration of inflammatory cells was similar in both cohorts, a significant delay in the lymphatic clearance of Sdc-1(-/-) macrophages was observed. Moreover, we observed enhanced inflammation and greater burden of atherosclerotic plaques in ApoE(-/-)Sdc-1(-/-) mice maintained on a Western diet. These results demonstrate that defective motility in Sdc-1(-/-) macrophages promotes a persistent inflammatory state with relevance to the pathogenesis of atherosclerosis. © 2014 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 12/2014; 35(2). DOI:10.1161/ATVBAHA.114.304720 · 5.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The TAM receptors-Tyro3, Axl, and Mer-comprise a unique family of receptor tyrosine kinases, in that as a group they play no essential role in embryonic development. Instead, they function as homeostatic regulators in adult tissues and organ systems that are subject to continuous challenge and renewal throughout life. Their regulatory roles are prominent in the mature immune, reproductive, hematopoietic, vascular, and nervous systems. The TAMs and their ligands-Gas6 and Protein S-are essential for the efficient phagocytosis of apoptotic cells and membranes in these tissues; and in the immune system, theyact as pleiotropic inhibitors of the innate inflammatory response to pathogens. Deficiencies in TAM signaling are thought to contribute to chronic inflammatory and autoimmune disease in humans, and aberrantly elevated TAM signaling is strongly associated with cancer progression, metastasis, and resistance to targeted therapies.
    Cold Spring Harbor perspectives in biology 11/2013; 5(11):a009076-a009076. DOI:10.1101/cshperspect.a009076 · 8.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Modulation of immune responses may form a powerful approach to treat atherosclerosis. It was shown that clearance of apoptotic cells results in tolerance induction to cleared Ags by dendritic cells (DCs); however, this seems impaired in atherosclerosis because Ag-specific tolerance is lacking. This could result, in part, from decreased emigration of DCs from atherosclerotic lesions because of the high-cholesterol environment. Nonetheless, local induction of anti-inflammatory responses by apoptotic cell clearance seems to dampen atherosclerosis, because inhibition of apoptotic cell clearance worsens atherosclerosis. In this study, we assessed whether i.v. administration of oxLDL-induced apoptotic DCs (apop(ox)-DCs) and, as a control, unpulsed apoptotic DCs could modulate atherosclerosis by inducing tolerance. Adoptive transfer of apop(ox)-DCs into low-density lipoprotein receptor knockout mice either before or during feeding of a Western-type diet resulted in increased numbers of CD103(+) tolerogenic splenic DCs, with a concomitant increase in regulatory T cells. Interestingly, both types of apoptotic DCs induced an immediate 40% decrease in Ly-6C(hi) monocyte numbers and a 50% decrease in circulating CCL2 levels, but only apop(ox)-DC treatment resulted in long-term effects on monocytes and CCL2 levels. Although initial lesion development was reduced by 40% in both treatment groups, only apop(ox)-DC treatment prevented lesion progression by 28%. Moreover, progressed lesions of apop(ox)-DC-treated mice showed a robust 45% increase in collagen content, indicating an enhanced stability of lesions. Our findings clearly show that apoptotic DC treatment significantly decreases lesion development, but only apop(ox)-DCs can positively modulate lesion progression and stability. These findings may translate into a safe treatment for patients with established cardiovascular diseases using patient-derived apop(ox)-DCs. Copyright © 2015 by The American Association of Immunologists, Inc.

Full-text (2 Sources)

Download
52 Downloads
Available from
May 29, 2014