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Johannes Birtel, Tobias Eisenberger, Martin Gliem, Philipp L Müller, Philipp Herrmann, Christian Betz, Diana Zahnleiter, Christine Neuhaus, Steffen Lenzner, Frank G Holz, Elisabeth Mangold, Hanno J Bolz, Peter Charbel Issa
Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions...
March 19, 2018: Scientific Reports
Cunzhen Shi, Xiangqun Li, Xiaogan Wang, Ning Ding, Lingyan Ping, Yunfei Shi, Lan Mi, Yumei Lai, Yuqin Song, Jun Zhu
BACKGROUND: Mantle cell lymphoma (MCL) is an incurable B cell-derived malignant tumor with a median overall survival of 4-5 years. Mer tyrosine kinase (MerTK) has been reported to be aberrantly expressed in leukemia, melanoma, and gastric cancer, and plays a pivotal role in the process of oncogenesis. This study assessed the role of MerTK in MCL for the first time. METHODS: Immunohistochemistry and western blot were performed to figure out expression of MerTK in MCL...
March 20, 2018: Journal of Hematology & Oncology
Hyojin Eom, Neha Kaushik, Ki-Chun Yoo, Jin-Kyoung Shim, Munjin Kwon, Mi-Young Choi, Taeyoung Yoon, Seok-Gu Kang, Su-Jae Lee
Receptor tyrosine kinase Mer (MerTK) has been shown to be highly expressed in Glioblastoma multiforme (GBM) in comparison to its healthy counterpart and is implicated in brain tumorigenesis. Clarifying the underlying mechanism of MerTK induced invasiveness would result in novel strategies to improve patient's response to chemotherapeutics. In vitro and in vivo assays were performed to examine the functional role of cancer stem sell (CSC) maintenance in MerTK associated invasiveness. In this article, we demonstrate that apart from GBM cells, MerTK is also upregulated in GBM stem-like cells and associated with an increased infiltrative potential of brain tumors in vivo...
March 19, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Delphine Lumbroso, Soaad Soboh, Avi Maimon, Sagie Schif-Zuck, Amiram Ariel, Tal Burstyn-Cohen
The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL, and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood...
2018: Frontiers in Immunology
Kyoung A Jhang, Jin-Sun Park, Hee-Sun Kim, Young Hae Chong
BACKGROUND: Mer tyrosine kinase (MerTK) activity necessary for amyloid-stimulated phagocytosis strongly implicates that MerTK dysregulation might contribute to chronic inflammation implicated in Alzheimer's disease (AD) pathology. However, the precise mechanism involved in the regulation of MerTK expression by amyloid-β (Aβ) in proinflammatory environment has not yet been ascertained. METHODS: The objective of this study was to determine the underlying mechanism involved in Aβ-mediated decrease in MerTK expression through Aβ-mediated regulation of MerTK expression and its modulation by sulforaphane in human THP-1 macrophages challenged with Aβ1-42...
March 12, 2018: Journal of Neuroinflammation
Bridget Shafit-Zagardo, Ross C Gruber, Juwen C DuBois
Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6)...
March 4, 2018: Pharmacology & Therapeutics
Amir Tajbakhsh, Mehdi Rezaee, Petri T Kovanen, Amirhossein Sahebkar
Atherosclerosis is a dynamic and progressive inflammatory process in the intimal layer of large and medium-sized arteries, and it is the major contributor to the atherosclerotic cardiovascular disease (ACVD), the leading cause of death worldwide. In an atherosclerotic plaque, phagocytosis of apoptotic cells occurs through an intricate process designated efferocytosis. Defective efferocytosis has emerged as a causal factor in the etiopathogenesis of atherosclerosis and its progression into overt ACVD. Both specialized phagocytes (macrophages and dendritic cells) and non-specialized cells with phagocytic capabilities (smooth muscle and endothelial cells) are involved in the efferocytotic process...
February 11, 2018: Pharmacology & Therapeutics
Mu Yang, Shujin Li, Wenjing Liu, Yeming Yang, Lin Zhang, Shanshan Zhang, Zhilin Jiang, Zhenglin Yang, Xianjun Zhu
BACKGROUND: Retinitis pigmentosa (RP) is a group of inherited retinal diseases that result in severe progressive visual impairment. AIMS: The purpose of this article was to apply targeted next-generation sequencing (NGS) to identify the causative mutation in a Chinese RP family. METHODS: Blood samples were collected from a Chinese proband diagnosed with RP and her family members. A total of 163 genes that have been previously found to be involved in inherited retinal diseases were selected for NGS...
February 13, 2018: Genetic Testing and Molecular Biomarkers
Sehwon Koh, William J Chen, Nadine S Dejneka, Ian R Harris, Bin Lu, Sergey Girman, Joshua Saylor, Shaomei Wang, Cagla Eroglu
Human umbilical tissue-derived cells (hUTC or palucorcel) are currently under clinical investigation for the treatment of geographic atrophy, a late stage of macular degeneration, but how hUTC transplantation mediates vision recovery is not fully elucidated. Subretinal administration of hUTC preserves visual function in the Royal College of Surgeons (RCS) rat, a genetic model of retinal degeneration caused by Mertk loss-of-function. hUTC secrete synaptogenic and neurotrophic factors that improve the health and connectivity of the neural retina...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Marianne A Bryan, Daniela Giordano, Kevin E Draves, Richard Green, Michael Gale, Edward A Clark
Although the spleen is a major site for West Nile virus (WNV) replication and spread, relatively little is known about which innate cells in the spleen replicate WNV, control viral dissemination, and/or prime innate and adaptive immune responses. Here we tested if splenic macrophages (MΦs) were necessary for control of WNV infection. We selectively depleted splenic MΦs, but not draining lymph node MΦs, by injecting mice intravenously with clodronate liposomes several days prior to infecting them with WNV...
2018: PloS One
Aleksander M Grabiec, Anu Goenka, Mark E Fife, Toshifumi Fujimori, Tracy Hussell
The requirement to remove apoptotic cells is equally important in homeostasis and inflammatory disease. In particular, during viral infections large quantities of infected cells undergo apoptosis and need to be efficiently cleared by phagocytes to prevent secondary necrosis. Although specific roles of several apoptotic cell sensors, such as the TAM (Tyro3, Axl, MerTK) receptor family, have been characterized in mouse models, little is known about their regulation and involvement in apoptotic cell uptake (efferocytosis) by human macrophages under inflammatory conditions...
February 5, 2018: European Journal of Immunology
Luke M Healy, Jeong Ho Jang, So-Yoon Won, Yun Hsuan Lin, Hanane Touil, Salman Aljarallah, Amit Bar-Or, Jack P Antel
Objective: To document functional differences between monocyte-derived macrophages (MDMs) of patients with MS and the ability of age/sex-matched healthy donor cells to phagocytose human myelin and to investigate the molecular mechanisms that underlie this. Methods: MDMs were derived from peripheral blood monocytes of 25 untreated patients with relapsing-remitting MS and secondary progressive MS and age/sex-matched healthy controls (HCs). Phagocytosis was assessed by flow cytometry using fluorescently labeled human myelin...
November 2017: Neurology® Neuroimmunology & Neuroinflammation
Woo Jin Kim, Hyo Jin Park, Yang Ji Choi, Eun Young Kwon, Bo Min Kim, Jin Hwa Lee, Jung Hyun Chang, Jihee Lee Kang, Ji Ha Choi
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease. To date, a large number of clinical studies have been conducted to investigate the association between genetic variations and COPD. However, little is known regarding the genetic susceptibility of Koreans to this disease. MER receptor tyrosine kinase (MERTK) plays important roles in the inhibition of inflammation and in the clearance of apoptotic cells. Here, we investigated the association between genetic variations in MERTK and the development of COPD in Koreans...
February 12, 2018: Journal of Korean Medical Science
Melissa J Mulla, Ingrid C Weel, Julie A Potter, Stefan M Gysler, Jane E Salmon, Maria T S Peraçoli, Carla V Rothlin, Lawrence W Chamley, Vikki M Abrahams
OBJECTIVE: Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications associated with poor placentation and placental inflammation. While these antibodies are heterogeneous, some anti-β2 GPI antibodies can activate human first trimester trophoblast TLR4 and NLRP3. The objective of this study was to determine the role of negative regulators of TLR and inflammasome function in aPL-induced trophoblast inflammation. METHODS: Human trophoblast cells were treated with or without anti-β2 GPI aPL or control IgG in the presence or absence of the common TAM receptor ligand, GAS6, or the autophagy inducer, rapamycin...
January 17, 2018: Arthritis & Rheumatology
Yeon-Joo Jung, Won-Suk Chung
Glial cells are receiving much attention since they have been recognized as important regulators of many aspects of brain function and disease. Recent evidence has revealed that two different glial cells, astrocytes and microglia, control synapse elimination under normal and pathological conditions via phagocytosis. Astrocytes use the MEGF10 and MERTK phagocytic pathways, and microglia use the classical complement pathway to recognize and eliminate unwanted synapses. Notably, glial phagocytosis also contributes to the clearance of disease-specific protein aggregates, such as β-amyloid, huntingtin, and α-synuclein...
January 10, 2018: Biomolecules & Therapeutics
Ayako Sayama, Keiko Okado, Koichi Nakamura, Tatsuya Kawaguchi, Takuma Iguchi, Toshihiko Makino, Koichi Yabe, Kiyonori Kai, Kazuhiko Mori
Mer proto-oncogene tyrosine kinase (MerTK), which is expressed in the retinal pigment epithelium (RPE), regulates phagocytosis of shed photoreceptor outer segments (POS). To investigate the effects of drug-induced MerTK inhibition on the retina, UNC569, a specific MerTK inhibitor, was orally administered to male mice at a concentration of 60, 100, or 150 mg/kg for up to 14 days. Furthermore, MerTK inhibition in the retinal tissue sample was examined using a phosphorylation assay following a single dose of UNC569 at 100 mg/kg...
January 1, 2018: Toxicologic Pathology
Hasenin Al-Khersan, Alan Kwong, Michael A Grassi
PURPOSE: To assess whether mutations in Mer tyrosine kinase (MERTK) are associated with age-related macular degeneration (AMD). METHODS: An association study using whole-genome sequencing was performed to determine whether rare variants in MERTK are associated with AMD. The data set included 4787 propensity score-matched case-control samples: 2394 AMD cases and 2393 controls. Whole-genome sequencing was performed and variants in MERTK were identified. Combined annotation-dependent depletion (CADD) scores and allele frequencies were calculated for each variant identified in MERTK...
January 3, 2018: International Ophthalmology
Jung Eun Kim, Youjin Kim, Gary Li, Seung Tae Kim, Kyung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Tae Sung Sohn, Kyoung-Mee Kim, Won Ki Kang, Jeeyun Lee
RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment...
December 1, 2017: Oncotarget
Yuki Koda, Mai Itoh, Shuji Tohda
BACKGROUND: MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells. MATERIALS AND METHODS: Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated...
January 2018: Anticancer Research
Che-Feng Chang, Brittany A Goods, Michael H Askenase, Matthew D Hammond, Stephen C Renfroe, Arthur F Steinschneider, Margaret J Landreneau, Youxi Ai, Hannah E Beatty, Luís Henrique Angenendt da Costa, Matthias Mack, Kevin N Sheth, David M Greer, Anita Huttner, Daniel Coman, Fahmeed Hyder, Sourav Ghosh, Carla V Rothlin, J Christopher Love, Lauren H Sansing
Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery...
December 18, 2017: Journal of Clinical Investigation
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