Cleavage of Mer Tyrosine Kinase (MerTK) from the Cell Surface Contributes to the Regulation of Retinal Phagocytosis

Law, Ah-Lai; Parinot, Célia; Chatagnon, Jonathan; Gravez, Basile; Sahel, José‐Alain; Bhattacharya, Siladitya; Nandrot, Emeline F.

doi:10.1074/jbc.m114.628297

Cited by 51 publications

(68 citation statements)

References 50 publications

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“…Phagocytosis of POS involves engagement of the actin–myosin cytoskeleton via the Mer/TK signalling complex whose activation controls the binding of POS to the RPE surface (Law et al ., 2015) under the control of a recently reported regulatory gene, Klotho (Kokkinaki et al ., 2013), while signalling via MerTK/Axl/Gas6 is required for phagocytosis of apoptotic cells in macrophages (Zagorska et al ., 2014). However, the process of cytokinesis depends on much more extensive changes to the actomyosin/tubulin cytoarchitecture involving inhibition of centrosome polarization (Schiebel, 2000), and indeed, the close relationship between mutlinucleation and cytokinesis was confirmed in the present work where treatment with blebbistatin prevented cytokinesis in nearly 50% ARPE19 cells, and many cells became multinucleated.…”

Section: Discussionmentioning

confidence: 99%

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

et al. 2016

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SummaryRetinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age‐related retinal degenerative disorders particularly age‐related macular degeneration. During aging RPE cells decline in number, suggesting an age‐dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose‐dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted ‘postmitotic’ status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long‐standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age‐related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells.

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Section: Discussionmentioning

confidence: 99%

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

et al. 2016

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“…It is thought that RPE cells share similar clearance mechanisms to those used by other phagocytes (e.g., macrophages and dendritic cells) to phagocytose shedded POS [3] . Previous studies have shown that certain receptors on RPE cells, such as common phagocyte receptor (TAM receptor tyrosine kinase Mer) [26][27][28] , scavenger receptor (CD36) [29] , and the integrin adhesion receptor (ανβ5) [30] , are involved in the phagocytosis of shedded POS. However, little is known about the involvement of opsonization-mediated phagocytosis (a well-known mechanism in macrophages) in RPE cells.…”

Section: Discussionmentioning

confidence: 99%

Collectin-11 Is an Important Modulator of Retinal Pigment Epithelial Cell Phagocytosis and Cytokine Production

Dong¹,

Wu²,

Ma³

et al. 2017

J Innate Immun

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In this paper, we report previously unknown roles for collectin-11 (CL-11, a soluble C-type lectin) in modulating the retinal pigment epithelial (RPE) cell functions of phagocytosis and cytokine production. We found that CL-11 and its carbohydrate ligand are expressed in both the murine and human neural retina; these resemble each other in terms of RPE and photoreceptor cells. Functional analysis of murine RPE cells showed that CL-11 facilitates the opsonophagocytosis of photoreceptor outer segments and apoptotic cells, and also upregulates IL-10 production. Mechanistic analysis revealed that calreticulin on the RPE cells is required for CL-11-mediated opsonophagocytosis whereas signal-regulatory protein α and mannosyl residues on the cells are involved in the CL-11-mediated upregulation of IL-10 production. This study is the first to demonstrate the role of CL-11 and the molecular mechanisms involved in modulating RPE cell phagocytosis and cytokine production. It provides a new insight into retinal health and disease and has implications for other phagocytic cells.

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“…In addition, the kinase domain contains three autophosphorylation sites (Tyr‐749, Tyr‐753, Tyr‐754), which are critical for its full activity (Ling, Templeton, & Kung, ). MERTK exists as a membrane‐bound receptor and as a soluble form (Sather et al., ) through its cleavage at proline 485 by ADAM17 (MIM# 603639), at least in murine macrophages and RPE cells (Law et al, ; Thorp et al., ). This soluble form would act as a negative feedback loop limiting POS binding to RPE cell surface prior to phagocytosis (Nandrot et al, ).…”

Section: Introductionmentioning

confidence: 99%

MERTK mutation update in inherited retinal diseases

et al. 2018

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MER tyrosine kinase (MERTK) encodes a surface receptor localized at the apical membrane of the retinal pigment epithelium. It plays a critical role in photoreceptor outer segment internalization prior to phagocytosis. Mutations in MERTK have been associated with severe autosomal recessive retinal dystrophies in the RCS rat and in humans. We present here a comprehensive review of all reported MERTK disease causing variants with the associated phenotype. In addition, we provide further data and insights of a large cohort of 1,195 inherited retinal dystrophies (IRD) index cases applying state-of-the-art genotyping techniques and summarize current knowledge. A total of 79 variants have now been identified underlying rod-cone dystrophy and cone-rod dystrophy including 11 novel variants reported here. The mutation spectrum in MERTK includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, two small insertion-deletions, three small duplications, and two exonic and three gross deletions. Altogether, mutations in MERTK account for ∼2% of IRD cases with a severe retinal phenotype. These data are important for current and future therapeutic trials including gene replacement therapy or cell-based therapy.

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Cleavage of Mer Tyrosine Kinase (MerTK) from the Cell Surface Contributes to the Regulation of Retinal Phagocytosis

Cited by 51 publications

References 50 publications

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

Collectin-11 Is an Important Modulator of Retinal Pigment Epithelial Cell Phagocytosis and Cytokine Production

MERTK mutation update in inherited retinal diseases

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