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Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway.
Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, Lucas CD, Onengut-Gumuscu S, Delpire E, Ravichandran KS
(2019) Nat Cell Biol 21: 1532-1543
MeSH Terms: Animals, Apoptosis, Biological Transport, Cell Line, Cell Line, Tumor, Chlorides, Humans, Inflammation, Jurkat Cells, Mice, Mice, Inbred C57BL, Oxidative Stress, Phagocytes, Phagocytosis, Signal Transduction, Sodium-Potassium-Chloride Symporters, Transcription, Genetic
Show Abstract · Added March 18, 2020
Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte 'appetite' and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This 'switch' to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK-which function upstream of SLC12A2-had a similar effect on efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.
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Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein.
Gilchuk P, Kuzmina N, Ilinykh PA, Huang K, Gunn BM, Bryan A, Davidson E, Doranz BJ, Turner HL, Fusco ML, Bramble MS, Hoff NA, Binshtein E, Kose N, Flyak AI, Flinko R, Orlandi C, Carnahan R, Parrish EH, Sevy AM, Bombardi RG, Singh PK, Mukadi P, Muyembe-Tamfum JJ, Ohi MD, Saphire EO, Lewis GK, Alter G, Ward AB, Rimoin AW, Bukreyev A, Crowe JE
(2018) Immunity 49: 363-374.e10
MeSH Terms: 3T3 Cells, Adult, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, CHO Cells, Cell Line, Chlorocebus aethiops, Cricetulus, Disease Models, Animal, Drosophila, Ebolavirus, Female, Ferrets, Glycoproteins, Guinea Pigs, Hemorrhagic Fever, Ebola, Humans, Immunoglobulin G, Jurkat Cells, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, THP-1 Cells, Vero Cells
Show Abstract · Added March 3, 2020
Ebolaviruses cause severe disease in humans, and identification of monoclonal antibodies (mAbs) that are effective against multiple ebolaviruses are important for therapeutics development. Here we describe a distinct class of broadly neutralizing human mAbs with protective capacity against three ebolaviruses infectious for humans: Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) viruses. We isolated mAbs from human survivors of ebolavirus disease and identified a potent mAb, EBOV-520, which bound to an epitope in the glycoprotein (GP) base region. EBOV-520 efficiently neutralized EBOV, BDBV, and SUDV and also showed protective capacity in relevant animal models of these infections. EBOV-520 mediated protection principally by direct virus neutralization and exhibited multifunctional properties. This study identified a potent naturally occurring mAb and defined key features of the human antibody response that may contribute to broad protection. This multifunctional mAb and related clones are promising candidates for development as broadly protective pan-ebolavirus therapeutic molecules.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.
Dovey CM, Diep J, Clarke BP, Hale AT, McNamara DE, Guo H, Brown NW, Cao JY, Grace CR, Gough PJ, Bertin J, Dixon SJ, Fiedler D, Mocarski ES, Kaiser WJ, Moldoveanu T, York JD, Carette JE
(2018) Mol Cell 70: 936-948.e7
MeSH Terms: Binding Sites, Cell Death, Colonic Neoplasms, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HT29 Cells, Herpesvirus 1, Human, Humans, Inositol Phosphates, Jurkat Cells, Mutation, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Tumor Necrosis Factor-alpha
Show Abstract · Added March 30, 2020
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.
Salina AC, Souza TP, Serezani CH, Medeiros AI
(2017) Innate Immun 23: 219-227
MeSH Terms: Animals, Apoptosis, Bacteriolysis, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Female, Homeostasis, Humans, Hydrogen Peroxide, Jurkat Cells, Macrophages, Alveolar, Phagocytosis, Pneumococcal Infections, Rats, Rats, Wistar, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of HO production. Our data suggest that the PGE produced by AMs during efferocytosis inhibits HO production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.
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20 MeSH Terms
Single cell analysis of human tissues and solid tumors with mass cytometry.
Leelatian N, Doxie DB, Greenplate AR, Mobley BC, Lehman JM, Sinnaeve J, Kauffmann RM, Werkhaven JA, Mistry AM, Weaver KD, Thompson RC, Massion PP, Hooks MA, Kelley MC, Chambless LB, Ihrie RA, Irish JM
(2017) Cytometry B Clin Cytom 92: 68-78
MeSH Terms: Antigens, CD, Flow Cytometry, HLA-DR Antigens, Humans, Jurkat Cells, Leukocyte Common Antigens, Neoplasms, Single-Cell Analysis
Show Abstract · Added September 7, 2016
BACKGROUND - Mass cytometry measures 36 or more markers per cell and is an appealing platform for comprehensive phenotyping of cells in human tissue and tumor biopsies. While tissue disaggregation and fluorescence cytometry protocols were pioneered decades ago, it is not known whether established protocols will be effective for mass cytometry and maintain cancer and stromal cell diversity.
METHODS - Tissue preparation techniques were systematically compared for gliomas and melanomas, patient derived xenografts of small cell lung cancer, and tonsil tissue as a control. Enzymes assessed included DNase, HyQTase, TrypLE, collagenase (Col) II, Col IV, Col V, and Col XI. Fluorescence and mass cytometry were used to track cell subset abundance following different enzyme combinations and treatment times.
RESULTS - Mechanical disaggregation paired with enzymatic dissociation by Col II, Col IV, Col V, or Col XI plus DNase for 1 h produced the highest yield of viable cells per gram of tissue. Longer dissociation times led to increasing cell death and disproportionate loss of cell subsets. Key markers for establishing cell identity included CD45, CD3, CD4, CD8, CD19, CD64, HLA-DR, CD11c, CD56, CD44, GFAP, S100B, SOX2, nestin, vimentin, cytokeratin, and CD31. Mass and fluorescence cytometry identified comparable frequencies of cancer cell subsets, leukocytes, and endothelial cells in glioma (R = 0.97), and tonsil (R = 0.98).
CONCLUSIONS - This investigation establishes standard procedures for preparing viable single cell suspensions that preserve the cellular diversity of human tissue microenvironments. © 2016 International Clinical Cytometry Society.
© 2016 International Clinical Cytometry Society.
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LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding.
Layer JH, Alford CE, McDonald WH, Davé UP
(2016) Mol Cell Biol 36: 488-506
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amino Acid Substitution, Cell Line, DNA-Binding Proteins, Humans, Jurkat Cells, LIM Domain Proteins, Leukemia, T-Cell, Molecular Sequence Data, Mutation, Protein Interaction Domains and Motifs, Protein Interaction Maps, Protein Stability, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation
Show Abstract · Added January 26, 2016
LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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17 MeSH Terms
Immunomodulatory metabolites released by the frog-killing fungus Batrachochytrium dendrobatidis.
Rollins-Smith LA, Fites JS, Reinert LK, Shiakolas AR, Umile TP, Minbiole KP
(2015) Infect Immun 83: 4565-70
MeSH Terms: Adenosine, Animals, Apoptosis, Cell Survival, Chytridiomycota, Drug Synergism, Host-Pathogen Interactions, Humans, Jurkat Cells, Kynurenine, Lymphocytes, Mycoses, Skin, Thionucleosides, Tryptophan, Xenopus laevis
Show Abstract · Added April 18, 2017
Batrachochytrium dendrobatidis is a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, but B. dendrobatidis releases factors that inhibit in vitro and in vivo lymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced by B. dendrobatidis but not by the closely related nonpathogenic chytrid Homolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize that B. dendrobatidis can adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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16 MeSH Terms
Methotrexate-mediated inhibition of nuclear factor κB activation by distinct pathways in T cells and fibroblast-like synoviocytes.
Spurlock CF, Gass HM, Bryant CJ, Wells BC, Olsen NJ, Aune TM
(2015) Rheumatology (Oxford) 54: 178-87
MeSH Terms: Adult, Aged, Apoptosis, Arthritis, Rheumatoid, Biopterin, Case-Control Studies, Cell Line, Female, Fibroblasts, Humans, Jurkat Cells, MAP Kinase Kinase 4, Male, Methotrexate, Middle Aged, NF-kappa B, Reactive Oxygen Species, Signal Transduction, Synovial Membrane
Show Abstract · Added January 21, 2015
OBJECTIVES - Nuclear factor κB (NF-κB) is a critical activator of inflammatory processes and MTX is one of the most commonly prescribed DMARDs for treatment of RA. We sought to determine whether MTX inhibited NF-κB activity in RA and in lymphocytes and fibroblast-like synoviocytes (FLSs) and to define underlying mechanisms of action.
METHODS - An NF-κB luciferase reporter plasmid was used to measure NF-κB activation across experimental stimuli. Flow cytometry was used to quantify changes in intracellular protein levels, measure levels of reactive oxygen species and determine apoptosis. Quantitative RT-PCR was used to identify changes in MTX target genes.
RESULTS - In T cell lines, MTX (0.1 μM) inhibited activation of NF-κB via depletion of tetrahydrobiopterin (BH4) and increased Jun-N-terminal kinase (JNK)-dependent p53 activity. Inhibitors of BH4 activity or synthesis also inhibited NF-κB activation and, similar to MTX, increased JNK, p53, p21 and JUN activity. Patients with RA expressed increased levels of phosphorylated or active RelA (p65) compared with controls. Levels of phosphorylated RelA were reduced in patients receiving low-dose MTX therapy. In contrast, inhibition of NF-κB activation by MTX was not mediated via BH4 depletion and JNK activation in FLSs, but rather was completely prevented by adenosine receptor antagonists.
CONCLUSION - Our findings support a model whereby distinct pathways are activated by MTX in T cells and FLSs to inhibit NF-κB activation.
© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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19 MeSH Terms
Molecular imaging of human tumor cells that naturally overexpress type 2 cannabinoid receptors using a quinolone-based near-infrared fluorescent probe.
Wu Z, Shao P, Zhang S, Ling X, Bai M
(2014) J Biomed Opt 19: 76016
MeSH Terms: Biomarkers, Tumor, Fluorescent Dyes, Humans, Jurkat Cells, Molecular Imaging, Molecular Probes, Quinolones, Receptor, Cannabinoid, CB2
Show Abstract · Added April 2, 2019
Cannabinoid CB2 receptors (CB2R) hold promise as therapeutic targets for treating diverse diseases, such as cancers, neurodegenerative diseases, pain, inflammation, osteoporosis, psychiatric disorders, addiction, and immune disorders. However, the fundamental role of CB2R in the regulation of diseases remains unclear, largely due to a lack of reliable imaging tools for the receptors. The goal of this study was to develop a CB2R-targeted molecular imaging probe and evaluate the specificity of the probe using human tumor cells that naturally overexpress CB2R. To synthesize the CB2R-targeted probe (NIR760-Q), a conjugable CB2R ligand based on the quinolone structure was first prepared, followed by bioconjugation with a near-infrared (NIR) fluorescent dye, NIR760. In vitro fluorescence imaging and competitive binding studies showed higher uptake of NIR760-Q than free NIR760 dye in Jurkat human acute T-lymphoblastic leukemia cells. In addition, the high uptake of NIR760-Q was significantly inhibited by the blocking agent, 4-quinolone-3-carboxamide, indicating specific binding of NIR760-Q to the target receptors. These results indicate that the NIR760-Q has potential in diagnostic imaging of CB2R positive cancers and elucidating the role of CB2R in the regulation of disease progression.
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The microfluidic multitrap nanophysiometer for hematologic cancer cell characterization reveals temporal sensitivity of the calcein-AM efflux assay.
Byrd TF, Hoang LT, Kim EG, Pfister ME, Werner EM, Arndt SE, Chamberlain JW, Hughey JJ, Nguyen BA, Schneibel EJ, Wertz LL, Whitfield JS, Wikswo JP, Seale KT
(2014) Sci Rep 4: 5117
MeSH Terms: Animals, Calcium-Binding Proteins, Cell Separation, Equipment Design, Equipment Failure Analysis, Flow Cytometry, Fluoresceins, Humans, Jurkat Cells, Leukemia, T-Cell, Microfluidic Analytical Techniques, Nanotechnology, Optical Tweezers, Reproducibility of Results, Sensitivity and Specificity, Tissue Array Analysis
Show Abstract · Added February 2, 2015
Cytometric studies utilizing flow cytometry or multi-well culture plate fluorometry are often limited by a deficit in temporal resolution and a lack of single cell consideration. Unfortunately, many cellular processes, including signaling, motility, and molecular transport, occur transiently over relatively short periods of time and at different magnitudes between cells. Here we demonstrate the multitrap nanophysiometer (MTNP), a low-volume microfluidic platform housing an array of cell traps, as an effective tool that can be used to study individual unattached cells over time with precise control over the intercellular microenvironment. We show how the MTNP platform can be used for hematologic cancer cell characterization by measuring single T cell levels of CRAC channel modulation, non-translational motility, and ABC-transporter inhibition via a calcein-AM efflux assay. The transporter data indicate that Jurkat T cells exposed to indomethacin continue to accumulate fluorescent calcein for over 60 minutes after calcein-AM is removed from the extracellular space.
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