Outer Segment Phagocytosis by Cultured Retinal Pigment Epithelial Cells Requires Gas6

Hall, Michael O.; Prieto, Anne L.; Obin, Martin S.; Abrams, Toshka A.; Burgess, Barry L.; Heeb, Mary J.; Agnew, Brian

doi:10.1006/exer.2001.1062

Cited by 84 publications

(61 citation statements)

References 49 publications

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“…Subsequent studies using MerTK knockout mice revealed that macrophages lacking MerTK are unable to ingest apoptotic thymocytes, either in vivo or in vitro (8,47). Previous work showed that gas6 is a ligand for MerTK, Tyro3, and Axl tyrosine kinases (34,48,49) and suggested that it stimulates photoreceptor outer segment phagocytosis by the retinal pigment epithelium (50). However, more recent studies found that gas6 knockout mice develop normal retina, suggesting the involvement of another molecule in MerTK-mediated phagocytosis of outer segment (18,19).…”

Section: Discussionmentioning

confidence: 99%

Auto-Oxidation and Oligomerization of Protein S on the Apoptotic Cell Surface Is Required for Mer Tyrosine Kinase-Mediated Phagocytosis of Apoptotic Cells

Uehara

Shacter

2008

The Journal of Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

Auto-Oxidation and Oligomerization of Protein S on the Apoptotic Cell Surface Is Required for Mer Tyrosine Kinase-Mediated Phagocytosis of Apoptotic Cells

Uehara

Shacter

2008

The Journal of Immunology

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“…The role of Mertk is not yet completely understood, but in RCS rats the RPE cells are deficient in Gas6 induced outer segment phagocytosis, implying that Mertk is a specific Gas6 receptor. 4 In the absence of functional Mertk, the RPE is unable to remove the shed outer segment membrane material, which then accumulates within the subretinal space. As a result, RPE and photoreceptors lose contact and consequently photoreceptor cells are lost and the retina degenerates.…”

Section: Introductionmentioning

confidence: 99%

Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

et al. 2005

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The Royal College of Surgeons (RCS) rat is a wellcharacterized model of autosomal recessive retinitis pigmentosa (RP) due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the gene encoding , a receptor tyrosine kinase found in RPE cells, that is required for phagocytosis of shed photoreceptor outer segments. The absence of Mertk results in accumulation of outer segment debris. This subsequently leads to progressive loss of photoreceptor cells. In order to evaluate the efficacy of lentiviral-mediated gene replacement therapy in the RCS rat, we produced recombinant VSV-G pseudotyped HIV-1-based lentiviruses containing a murine Mertk cDNA driven by a spleen focus forming virus (SFFV) promoter. The vector was subretinally injected into the right eye of 10-dayold RCS rats; the left eye was left untreated as an internal control. Here, we present a detailed assessment of the duration and extent of the morphological rescue and the resulting functional benefits. We examined animals at various time points over a period of 7 months by light and electron microscopy, and electroretinography. We observed correction of the phagocytic defect, slowing of photoreceptor cell loss and preservation of retinal function for up to 7 months. This study demonstrates the potential of gene therapy approaches for the treatment of retinal degenerations caused by defects specific to the RPE and supports the use of lentiviral vectors for the treatment of such disorders. Gene Therapy (2005) 12, 694-701.

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“…Interestingly, one intracellular signaling pathway that mediates mesangial cell proliferation occurs through signal transducer and activator of tranduction 3 (STAT3) activation (44). Other tissues where Gas6 may play a functional role include bone, where Gas6-Axl interactions upregulate osteoclast function (27,33), the central nervous system, where Gas6 protects neurons from amyloid-induced apoptosis (42), and the eye, where Gas6 mediates outer retinal pigment epithelial function (22,23). Finally, homozygous null Gas6 mice have a platelet dysfunction that protect mice against lethal intravascular thrombosis (1).…”

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confidence: 99%

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

Hasanbasic

Cuerquis²,

Varnum³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

131

125

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Gas6 is a γ-carboxylated ligand for the receptor tyrosine kinase Axl. Gas6-Axl interactions can rescue endothelial cells from apoptosis, and this study examined the intracellular signaling mechanisms responsible for this phenomenon. Using flow cytometry, we first confirmed that Gas6 can abrogate apoptosis induced by serum starvation of primary cultures of human umbilical vein endothelial cells (HUVECs). This effect is mediated through phosphorylation of the serine-threonine kinase Akt, with maximal phosphorylation observed after 4 h of treatment with 100 ng/ml Gas6. Inhibition of Akt phosphorylation and abrogation of gas6-mediated survival of HUVECs by wortmannin implicated phosphatidylinositol 3-kinase as the mediator of Akt phosphorylation. Dominant negative Akt constructs largely abrogated the protective effect of Gas6 on HUVECs, underscoring the importance of Akt activation in Gas6-mediated survival. Several downstream regulators of this survival pathway were identified in HUVECs, namely, NF-κB as well as the antiapoptotic and proapoptotic proteins Bcl-2 and caspase 3, respectively. We showed that NF-κB is phosphorylated early after Gas6 treatment as evidenced by doublet formation on Western blotting. As well, the level of Bcl-2 protein increased, supporting the notion that the Bcl-2 antiapoptotic pathway is stimulated. The levels of expression of the caspase 3 activation products p12 and p20 decreased with Gas6 treatment, consistent with a reduction in proapoptotic caspase 3 activation. Taken together, these experiments provide new information about the mechanism underlying Gas6 protection from apoptosis in primary endothelial cell cultures.

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Outer Segment Phagocytosis by Cultured Retinal Pigment Epithelial Cells Requires Gas6

Cited by 84 publications

References 49 publications

Auto-Oxidation and Oligomerization of Protein S on the Apoptotic Cell Surface Is Required for Mer Tyrosine Kinase-Mediated Phagocytosis of Apoptotic Cells

Auto-Oxidation and Oligomerization of Protein S on the Apoptotic Cell Surface Is Required for Mer Tyrosine Kinase-Mediated Phagocytosis of Apoptotic Cells

Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

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