Showing papers on "MERTK published in 2008"
TL;DR: Linkage analysis, homozygosity mapping and candidate gene analysis facilitated the identification of 14 genes mutated in patients with LCA and juvenile retinal degeneration, which together explain approximately 70% of the cases.
739 citations
TL;DR: Test the hypothesis that the MertkKD mutation would result in increased accumulation of apoptotic cells and promote necrotic core expansion in a mouse model of advanced atherosclerosis and suggest a novel therapeutic target to prevent advanced plaque progression and its clinical consequences.
Abstract: Conclusion—In a mouse model of advanced atherosclerosis, mutation of the phagocytic Mertk receptor promotes the accumulation of apoptotic cells and the formation of necrotic plaques. These data are consistent with the notion that a defect in an efferocytosis receptor can accelerate the progression of atherosclerosis and suggest a novel therapeutic target to prevent advanced plaque progression and its clinical consequences. (Arterioscler Thromb Vasc Biol. 2008;28:1421-1428)
313 citations
TL;DR: Mertk expression by bone marrow–derived cells is required for the disposal of apoptotic cells and controls lesion development and inflammation.
Abstract: Objective— To study the role of Mer receptor tyrosine kinase (mertk) in atherosclerosis.
Methods and Results— 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.
Conclusions— Mertk expression by bone marrow-derived cells is required for the disposal of apoptotic cells and controls lesion development and inflammation.
162 citations
TL;DR: Evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation is presented, demonstrating that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.
Abstract: Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTK(KD/KD)) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTK(KD/KD) versus NOD mice expressing the transgenic BDC T cell receptor. In addition, beta cell-specific CD4(+) T cells adoptively transferred into NOD.MerTK(KD/KD) mice in which beta cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c(+)CD8alpha(+) DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.
141 citations
TL;DR: Mertk post-receptor events that govern phagocytosis and cytoskeletal signaling are principally mediated by autophosphorylation site Tyr-867, providing a molecular rationale for how immune licensing and inflammation can be dissociated from phagcytosis in a singlePhagocytic receptor.
124 citations
TL;DR: During AC uptake by murine Mø, SR‐A is essential for optimal phosphorylation of Mertk and subsequent signaling required for AC ingestion, and these data support the MertK/SR‐A complex as a potential target to manipulate AC clearance and hence, resolution of inflammation and infections.
Abstract: Apoptotic cells (AC) must be cleared by macrophages (Mo) to resolve inflammation effectively. Mertk and scavenger receptor A (SR-A) are two of many receptors involved in AC clearance. As SR-A lacks enzymatic activity or evident intracellular signaling motifs, yet seems to signal in some cell types, we hypothesized that SR-A signals via Mer receptor tyrosine kinase (Mertk), which contains a multisubstrate docking site. We induced apoptosis in murine thymocytes by dexamethasone and used Western blotting and immunoprecipitation to analyze the interaction of Mertk and SR-A in the J774A.1 (J774) murine Mo cell line and in peritoneal Mo of wild-type mice and SR-A−/− mice. Phagocytosis (but not adhesion) of AC by J774 was inhibited by anti-SR-A or function-blocking SR-A ligands. In resting J774, SR-A was associated minimally with unphosphorylated (monomeric) Mertk; exposure to AC induced a time-dependent increase in association of SR-A with Mertk in a direct or indirect manner. Anti-SR-A inhibited AC-induced phosphorylation of Mertk and of phospholipase Cγ2, essential steps in AC ingestion. Relative to tissue Mo of wild-type mice, AC-induced Mertk phosphorylation was reduced and delayed in tissue Mo of SR-A−/− mice, as was in vitro AC ingestion at early time-points. Thus, during AC uptake by murine Mo, SR-A is essential for optimal phosphorylation of Mertk and subsequent signaling required for AC ingestion. These data support the Mertk/SR-A complex as a potential target to manipulate AC clearance and hence, resolution of inflammation and infections.
98 citations
TL;DR: GAS6 represents a new player in this context, while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.
Abstract: GAS6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. GAS6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition and having 40% sequence identity. Despite this, the low concentration of GAS6 in plasma and the pattern of tissue expression of GAS6 suggest a distinct function among vitamin-K dependent proteins. Indeed, GAS6 has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family;Tyro3,Axl and MerTK. GAS6 employs a unique mechanism of action, interacting through its vitamin K-dependent GLA (γ-carboxyglutamic acid) module with phosphatidylserine-containing membranes and through its carboxy-terminal LamG domains with the TAM membrane receptors. During the last years there has been a considerable expansion of our knowledge of the biology ofTAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. The innate immune response and the coagulation cascade have been shown to be interconnected. Mediators of inflammation are essential in the initiation and propagation of the coagulation cascade, while natural anticoagulants have important anti-inflammatory functions. GAS6 represents a new player in this context,while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.
85 citations
TL;DR: The data suggest that membranes containing phosphatidylserine serve as a scaffold for protein S-protein S interactions and that the resulting auto-oxidation and oligomerization is required for the prophagocytic activity of protein S, which helps apoptotic cells facilitate their own uptake by macrophages.
Abstract: Prompt phagocytosis of apoptotic cells prevents inflammatory and autoimmune responses to dying cells. We have previously shown that the blood anticoagulant factor protein S stimulates phagocytosis of apoptotic human B lymphoma cells by human monocyte-derived macrophages. In this study, we show that protein S must first undergo oxidative activation to stimulate phagocytosis. Binding of human protein S to apoptotic cells or to phosphatidylserine multilamellar vesicles promotes auto-oxidation of Cys residues in protein S, resulting in covalent, disulfide-linked dimers and oligomers that preferentially bind to and activate the human Mer tyrosine kinase (MerTK) receptor on the macrophages. The prophagocytic activity of protein S is eliminated when disulfide-mediated oligomerization is prevented, or when MerTK is blocked with neutralizing Abs. Protein S oligomerization is independent of phospholipid oxidation. The data suggest that membranes containing phosphatidylserine serve as a scaffold for protein S-protein S interactions and that the resulting auto-oxidation and oligomerization is required for the prophagocytic activity of protein S. In this way, apoptotic cells facilitate their own uptake by macrophages. The requirement for oxidative modification of protein S can explain why this abundant blood protein does not constitutively activate MerTK in circulating monocytes and tissue macrophages.
79 citations
TL;DR: Gas6 employs a unique mechanism of action, interacting through its vitamin K-dependent Gla module with phosphatidylserine-containing membranes and through its carboxy-terminal LG domains with the TAM membrane receptors, which are affected by anti-vitamin K therapy.
Abstract: Gas6 (growth arrest-specific gene 6) is the last addition to the family of plasma vitamin K-dependent proteins. Gas6 was cloned and characterized in 1993 and found to be similar to the plasma anticoagulant protein S. Soon after it was recognized as a growth factor-like molecule, as it interacted with receptor tyrosine kinases (RTKs) of the TAM family; Tyro3, Axl, and MerTK. Since then, the role of Gas6, protein S, and the TAM receptors has been found to be important in inflammation, hemostasis, and cancer, making this system an interesting target in biomedicine. Gas6 employs a unique mechanism of action, interacting through its vitamin K-dependent Gla module with phosphatidylserine-containing membranes and through its carboxy-terminal LG domains with the TAM membrane receptors. The fact that these proteins are affected by anti-vitamin K therapy is discussed in detail.
73 citations
TL;DR: These aspects of the macrophage in atherosclerotic lesion biology drive the progression of the disease and lead to the decomposition of the arterial wall into atheroma, the ugly gruel remaining after foam cell decomposition.
Abstract: The role of the macrophage is of fundamental interest in understanding atherosclerotic lesion development and thrombogenicity. After differentiation from blood peripheral monocytes, intimal macrophages incorporate modified lipoproteins through the scavenger receptor pathway.1 This transforms the macrophage into a lipid-rich foam cell which is a hallmark feature of atherosclerosis and leads to lesion expansion. Macrophage activation results in the excretion of proinflammatory and cytotoxic substances,2 including peroxynitrite, an early inducer of atherosclerosis through the endoplasmic reticulum (ER) stress pathway.3 Further, the accumulation of free cholesterol or uptake of oxidized LDL induces macrophage apoptosis.4 Cytokine release from macrophages augments the inflammatory response and increases lesion size. Cytotoxic substances, including peroxynitrite and tumor necrosis factor (TNF)-α, released by the macrophage results in cell death of lesion-resident endothelial and smooth muscle cells, thereby disrupting vessel structure. Macrophages can also alter the extracellular matrix of the vessel by releasing matrix metalloproteinases (MMPs), thereby leading to lesion breakdown and predisposing the lesion to fissure or rupture.5 These aspects of the macrophage in atherosclerotic lesion biology drive the progression of the disease and lead to the decomposition of the arterial wall into atheroma, the ugly gruel remaining after foam cell decomposition.
See accompanying articles on pages 1421 and 1429
The macrophage may also have good effects within the blood vessel wall. Macrophages remove debris through the process of phagocytosis.6 One aspect of macrophage phagocytosis, namely efferocytosis, is a process that prevents secondary necrosis and inflammation by removing apoptotic bodies before their decomposition.7 Efferocytosis has been shown to be mediated by 3 tyrosine kinase receptors, Axl, Tyro3, and Mer receptor tyrosine kinase (Mertk) in cells of hematopoietic lineage.8 Mertk is the primary mediator of efferocytosis in macrophages.9 Despite the presence of all 3 receptors on macrophages, Mertk has a …
62 citations
TL;DR: MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.
Abstract: Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AMs) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AMs obtained by bronchoalveolar lavage of normal nonsmokers (n = 11) and phenotypic normal smokers (n = 13; 36 +/- 6 pack-years) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER tyrosine kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AMs of smokers versus nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow analysis. Smoker AMs had up-regulation of MERTK mRNA levels (smoker vs. nonsmoker: 3.6-fold by microarray, P < 0.003; 9.5-fold by TaqMan RT-PCR, P < 0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AMs of smokers. Increased protein expression of MERTK on AMs of smokers was confirmed by Western and flow analyses (P < 0.007 and P < 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers. This up-regulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.
TL;DR: Results suggest that L-type Ca(2+)-channels could be regulated downstream of both MerTK and alphavbeta5-integrin, indicating that the binding and uptake mechanisms of phagocytosis are part of a converging pathway.
TL;DR: A novel MERTK mutation (IVS16+1G>T) in a Spanish consanguineous family presenting arRP disrupts the splice donor site causing exon 16 skipping and creates an altered mRNA transcript with a seriously affected tyrosine kinase domain.
Abstract: Background/aim: Mutations in MERTK, a member of the MER/AXL/TYR03 receptor kinase family, have been associated with disruption of the Retinal Pigment Epithelium (RPE) phagocytosis pathway and settling of autosomal recessive RP (arRP) in humans. This study reports a novel MERTK mutation (IVS16+1G>T) in a Spanish consanguineous family presenting arRP. Methods: 21 genes were screened by high-throughput SNP multiplexing assay. Subsequent direct sequencing was performed in exons and intronic boundaries of the cosegregating gene. The effect of the mutation in mRNA splicing was confirmed by cDNA analysis. Results: Haplotypic data revealed MERTK cosegregation with RP in affected individuals. MERTK sequencing showed a G-to-T substitution at the first nucleotide of intron 16. Finally, cDNA analysis confirmed the lack of exon 16 in the mRNA splicing process. Conclusions: IVS16+1G>T disrupts the splice donor site causing exon 16 skipping. Absence of exon 16 causes a frameshift and, subsequently, the introduction of a premature termination codon into exon 17 creating an altered mRNA transcript with a seriously affected tyrosine kinase domain.
TL;DR: In this article, the authors used transgenic mice that continuously overexpress the neurotrophin, NT-3, from lens fibers under the control of the αA-crystallin promoter to test for neuroprotection in light-damage experiments and in four naturally occurring or transgenically induced RDs in mice.
Abstract: Several neurotrophic factors (NTFs) are effective in protecting retinal photoreceptor cells from the damaging effects of constant light and slowing the rate of inherited photoreceptor degenerations. It is currently unclear whether, if continuously available, all NTFs can be protective for many or most retinal degenerations (RDs). We have used transgenic mice that continuously overexpress the neurotrophin, NT-3, from lens fibers under the control of the αA-crystallin promoter to test for neuroprotection in light-damage experiments and in four naturally occurring or transgenically induced RDs in mice. Lens-specific expression of NT-3 mRNA was demonstrated both by in situ hybridization in embryos and by RT-PCR in adult mice. Furthermore, NT-3 protein was found in abundance in the lens, ocular fluids and retina by ELISA and immunocytochemistry. Overexpression of NT-3 had no adverse effects on the structure or function of the retina for up to at least 14 months of age. Mice expressing the NT-3 transgene were protected from the damaging effects of constant light to a much greater degree than those receiving bolus injections of NT-3. When the NT-3 transgene was transferred into rd/rd, Rds/+, Q344ter mutant rhodopsin or Mertk knockout mice, overexpression of NT-3 had no protective effect on the RDs in these mice. Thus, specificity of the neuroprotective effect of NT-3 is clearly demonstrated, and different molecular mechanisms are inferred to mediate the protective effect in light-induced and inherited RDs.