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T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.
Josefsson SE, Huse K, Kolstad A, Beiske K, Pende D, Steen CB, Inderberg EM, Lingjærde OC, Østenstad B, Smeland EB, Levy R, Irish JM, Myklebust JH
(2018) Clin Cancer Res 24: 870-881
MeSH Terms: Antigens, Differentiation, T-Lymphocyte, CD8-Positive T-Lymphocytes, Cytokines, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, Follicular, Receptors, Antigen, T-Cell, Receptors, Immunologic, Signal Transduction, T-Lymphocyte Subsets, Tumor Microenvironment
Show Abstract · Added December 15, 2017
T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry. TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon culture. The costimulatory receptor CD226 was downregulated in TIGIT compared with TIGIT CD8 FL T cells, further skewing the balance toward immunosuppression. TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. .
©2017 American Association for Cancer Research.
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12 MeSH Terms
TGFβ loss activates ADAMTS-1-mediated EGF-dependent invasion in a model of esophageal cell invasion.
Le Bras GF, Taylor C, Koumangoye RB, Revetta F, Loomans HA, Andl CD
(2015) Exp Cell Res 330: 29-42
MeSH Terms: ADAM Proteins, ADAMTS1 Protein, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Movement, Cell Proliferation, Esophageal Neoplasms, Fibroblasts, Heparin-binding EGF-like Growth Factor, Humans, Interleukin-1, Keratinocytes, Nerve Tissue Proteins, Receptors, Immunologic, Receptors, Transforming Growth Factor beta, Transforming Growth Factor alpha, Transforming Growth Factor beta
Show Abstract · Added October 13, 2015
The TGFβ signaling pathway is essential to epithelial homeostasis and is often inhibited during progression of esophageal squamous cell carcinoma. Recently, an important role for TGFβ signaling has been described in the crosstalk between epithelial and stromal cells regulating squamous tumor cell invasion in mouse models of head-and-neck squamous cell carcinoma (HNSCC). Loss of TGFβ signaling, in either compartment, leads to HNSCC however, the mechanisms involved are not well understood. Using organotypic reconstruct cultures (OTC) to model the interaction between epithelial and stromal cells that occur in dysplastic lesions, we show that loss of TGFβ signaling promotes an invasive phenotype in both fibroblast and epithelial compartments. Employing immortalized esophageal keratinocytes established to reproduce common mutations of esophageal squamous cell carcinoma, we show that treatment of OTC with inhibitors of TGFβ signaling (A83-01 or SB431542) enhances invasion of epithelial cells into a fibroblast-embedded Matrigel/collagen I matrix. Invasion induced by A83-01 is independent of proliferation but relies on protease activity and expression of ADAMTS-1 and can be altered by matrix density. This invasion was associated with increased expression of pro-inflammatory cytokines, IL1 and EGFR ligands HB-EGF and TGFα. Altering EGF signaling prevented or induced epithelial cell invasion in this model. Loss of expression of the TGFβ target gene ROBO1 suggested that chemorepulsion may regulate keratinocyte invasion. Taken together, our data show increased invasion through inhibition of TGFβ signaling altered epithelial-fibroblasts interactions, repressing markers of activated fibroblasts, and altering integrin-fibronectin interactions. These results suggest that inhibition of TGFβ signaling modulates an array of pathways that combined promote multiple aspects of tumor invasion.
Copyright © 2014 Elsevier Inc. All rights reserved.
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17 MeSH Terms
TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis.
Yu S, Nie Y, Knowles B, Sakamori R, Stypulkowski E, Patel C, Das S, Douard V, Ferraris RP, Bonder EM, Goldenring JR, Ip YT, Gao N
(2014) EMBO J 33: 1882-95
MeSH Terms: Animals, Drosophila, Drosophila Proteins, Endosomes, Enterocytes, Gene Deletion, Homeostasis, Intestinal Mucosa, Mice, Microbiota, Receptors, Immunologic, Toll-Like Receptor 9, rab GTP-Binding Proteins
Show Abstract · Added March 28, 2016
Compartmentalization of Toll-like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a, a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell-intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild-type controls, germ-free Rab11a-deficient mouse intestines failed to tolerate the intraluminal stimulation of microbial agonists. Thus, Rab11a endosome controls intestinal host-microbial homeostasis at least partially via sorting TLRs.
© 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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13 MeSH Terms
Ascorbate reverses high glucose- and RAGE-induced leak of the endothelial permeability barrier.
Meredith ME, Qu ZC, May JM
(2014) Biochem Biophys Res Commun 445: 30-5
MeSH Terms: Acetylcysteine, Animals, Antioxidants, Ascorbic Acid, Benzamides, Cell Line, Cell Membrane Permeability, Cells, Cultured, Chromans, Cyclic N-Oxides, Dithiothreitol, Dose-Response Relationship, Drug, Endothelial Cells, Glucose, Glycation End Products, Advanced, HMGB1 Protein, Human Umbilical Vein Endothelial Cells, Humans, Mice, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Serum Albumin, Bovine, Spin Labels
Show Abstract · Added May 27, 2014
High glucose concentrations due to diabetes increase leakage of plasma constituents across the endothelial permeability barrier. We sought to determine whether vitamin C, or ascorbic acid (ascorbate), could reverse such high glucose-induced increases in endothelial barrier permeability. Human umbilical vein endothelial cells and two brain endothelial cell lines cultured at 25 mM glucose showed increases in endothelial barrier permeability to radiolabeled inulin compared to cells cultured at 5mM glucose. Acute loading of the cells for 30-60 min with ascorbate before the permeability assay prevented the high glucose-induced increase in permeability and decreased basal permeability at 5mM glucose. High glucose-induced barrier leakage was mediated largely by activation of the receptor for advanced glycation end products (RAGE), since it was prevented by RAGE blockade and mimicked by RAGE ligands. Intracellular ascorbate completely prevented RAGE ligand-induced increases in barrier permeability. The high glucose-induced increase in endothelial barrier permeability was also acutely decreased by several cell-penetrant antioxidants, suggesting that at least part of the ascorbate effect could be due to its ability to act as an antioxidant.
Copyright © 2014 Elsevier Inc. All rights reserved.
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23 MeSH Terms
BTLA as a biomarker and mediator of sepsis-induced immunosuppression.
Sherwood ER, Hotchkiss RS
(2013) Crit Care 17: 1022
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Cross Infection, Humans, Male, Receptors, Immunologic, Sepsis
Show Abstract · Added October 18, 2015
Recent research indicates that T-lymphocyte dysfunction may contribute to sepsis-associated morbidity and mortality. B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor expressed by T lymphocytes and B lymphocytes that is important in regulating lymphocyte activation during inflammation and infection. Shubin and colleagues report that higher mean BTLA expression in critically ill patients may have value in identifying patients with infection. Further studies provide evidence that BTLA activation contributes to T-lymphocyte apoptosis during sepsis. Although this study will require follow-up and further investigation, the results advance current knowledge regarding potential mechanisms underlying sepsis-induced immunosuppression and identify BTLA as a candidate biomarker and mediator of T-cell dysfunction during sepsis.
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7 MeSH Terms
α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.
Inman DM, Lambert WS, Calkins DJ, Horner PJ
(2013) PLoS One 8: e65389
MeSH Terms: Administration, Oral, Animals, Antioxidants, Axons, Cell Death, DNA Damage, Dietary Supplements, Drug Evaluation, Preclinical, Gene Expression, Glaucoma, Intraocular Pressure, Lipid Peroxidation, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Nerve Degeneration, Nitric Oxide Synthase Type II, Oxidation-Reduction, Oxidative Stress, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Retina, Retinal Ganglion Cells, Thioctic Acid, Treatment Outcome, Up-Regulation
Show Abstract · Added May 27, 2014
Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma. Similar to other neurodegenerative diseases, we observed lipid peroxidation and upregulation of oxidative stress-related mRNA and protein in DBA/2J retina. To test the role of oxidative stress in disease progression, we chose to deliver the naturally occurring, antioxidant α-lipoic acid (ALA) to DBA/2J mice in their diet. We used two paradigms for ALA delivery: an intervention paradigm in which DBA/2J mice at 6 months of age received ALA in order to intervene in glaucoma development, and a prevention paradigm in which DBA/2J mice were raised on a diet supplemented with ALA, with the goal of preventing glaucoma development. At 10 and 12 months of age (after 4 and 11 months of dietary ALA respectively), we measured changes in genes and proteins related to oxidative stress, retinal ganglion cell (RGC) number, axon transport, and axon number and integrity. Both ALA treatment paradigms showed increased antioxidant gene and protein expression, increased protection of RGCs and improved retrograde transport compared to control. Measures of lipid peroxidation, protein nitrosylation, and DNA oxidation in retina verified decreased oxidative stress in the prevention and intervention paradigms. These data demonstrate the utility of dietary therapy for reducing oxidative stress and improving RGC survival in glaucoma.
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26 MeSH Terms
Prostaglandin E2-induced changes in alveolar macrophage scavenger receptor profiles differentially alter phagocytosis of Pseudomonas aeruginosa and Staphylococcus aureus post-bone marrow transplant.
Domingo-Gonzalez R, Katz S, Serezani CH, Moore TA, Levine AM, Moore BB
(2013) J Immunol 190: 5809-17
MeSH Terms: Animals, Bone Marrow Transplantation, Dinoprostone, Gene Expression Regulation, Macrophages, Alveolar, Mice, MicroRNAs, Phagocytosis, Pseudomonas Infections, Pseudomonas aeruginosa, Receptors, Immunologic, Receptors, Scavenger, Scavenger Receptors, Class A, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added May 4, 2017
The effectiveness of hematopoietic stem cell transplantation as a therapy for malignant and nonmalignant conditions is complicated by pulmonary infections. Using our syngeneic bone marrow transplant (BMT) mouse model, BMT mice with a reconstituted hematopoietic system displayed increased susceptibility to Pseudomonas aeruginosa and Staphylococcus aureus. BMT alveolar macrophages (AMs) exhibited a defect in P. aeruginosa phagocytosis, whereas S. aureus uptake was surprisingly enhanced. We hypothesized that the difference in phagocytosis was due to an altered scavenger receptor (SR) profile. Interestingly, MARCO expression was decreased, whereas SR-AI/II was increased. To understand how these dysregulated SR profiles might affect macrophage function, CHO cells were transfected with SR-AI/II, and phagocytosis assays revealed that SR-AI/II was important for S. aureus uptake but not for P. aeruginosa. Conversely, AMs treated in vitro with soluble MARCO exhibited similar defects in P. aeruginosa internalization as did BMT AMs. The 3'-untranslated region of SR-AI contains a putative target region for microRNA-155 (miR-155), and miR-155 expression is decreased post-BMT. Anti-miR-155-transfected AMs exhibited an increase in SR-AI/II expression and S. aureus phagocytosis. Elevated PGE2 has been implicated in driving an impaired innate immune response post-BMT. In vitro treatment of AMs with PGE2 increased SR-AI/II and decreased MARCO and miR-155. Despite a difference in phagocytic ability, BMT AMs harbor a killing defect to both P. aeruginosa and S. aureus. Thus, our data suggest that PGE2-driven alterations in SR and miR-155 expression account for the differential phagocytosis of P. aeruginosa and S. aureus, but impaired killing ultimately confers increased susceptibility to pulmonary infection.
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15 MeSH Terms
Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.
Meloche J, Courchesne A, Barrier M, Carter S, Bisserier M, Paulin R, Lauzon-Joset JF, Breuils-Bonnet S, Tremblay É, Biardel S, Racine C, Courture C, Bonnet P, Majka SM, Deshaies Y, Picard F, Provencher S, Bonnet S
(2013) J Am Heart Assoc 2: e005157
MeSH Terms: Adult, Aged, Animals, Apoptosis, Arterial Pressure, Bone Morphogenetic Protein Receptors, Type II, Case-Control Studies, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Female, Glycation End Products, Advanced, Humans, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Indoles, Male, Middle Aged, Monocrotaline, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, PPAR gamma, Pulmonary Artery, Pyrroles, RNA Interference, Rats, Rats, Sprague-Dawley, Receptor for Advanced Glycation End Products, Receptors, Immunologic, S100 Proteins, STAT3 Transcription Factor, Signal Transduction, Transfection, Up-Regulation
Show Abstract · Added August 4, 2015
BACKGROUND - Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator-activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end-products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH-PASMC proliferation and resistance to apoptosis.
METHODS AND RESULTS - In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6-fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline- and Sugen-induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%).
CONCLUSION - We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.
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36 MeSH Terms
Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling.
Rai V, Touré F, Chitayat S, Pei R, Song F, Li Q, Zhang J, Rosario R, Ramasamy R, Chazin WJ, Schmidt AM
(2012) J Exp Med 209: 2339-50
MeSH Terms: Animals, Cell Line, Tumor, Cyclin D1, Female, Humans, Lysophospholipids, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle, Smooth, Vascular, Neoplasms, Proto-Oncogene Proteins c-akt, Rats, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Recombinant Proteins, Signal Transduction
Show Abstract · Added March 12, 2014
The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
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18 MeSH Terms
Structural basis for ligand recognition and activation of RAGE.
Koch M, Chitayat S, Dattilo BM, Schiefner A, Diez J, Chazin WJ, Fritz G
(2010) Structure 18: 1342-52
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, Humans, Hydrogen-Ion Concentration, Kinetics, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Nerve Growth Factors, Protein Binding, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Receptor for Advanced Glycation End Products, Receptors, Immunologic, S100 Calcium Binding Protein beta Subunit, S100 Proteins, Sequence Homology, Amino Acid
Show Abstract · Added March 12, 2014
The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling events upon binding of a variety of ligands, such as glycated proteins, amyloid-β, HMGB1, and S100 proteins. The X-ray crystal structure of the VC1 ligand-binding region of the human RAGE ectodomain was determined at 1.85 Å resolution. The VC1 ligand-binding surface was mapped onto the structure from titrations with S100B monitored by heteronuclear NMR spectroscopy. These NMR chemical shift perturbations were used as input for restrained docking calculations to generate a model for the VC1-S100B complex. Together, the arrangement of VC1 molecules in the crystal and complementary biochemical studies suggest a role for self-association in RAGE function. Our results enhance understanding of the functional outcomes of S100 protein binding to RAGE and provide insight into mechanistic models for how the receptor is activated.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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21 MeSH Terms