DOCSLIB.ORG

Immune Cells in Spleen and Mucosa + CD127 Neg Production of IL-17

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Immune Cells in Spleen and Mucosa + CD127 Neg Production of IL-17 Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 neg is online at: average * The Journal of Immunology published online 21 June 2010 Immune Cells in Spleen and Mucosa from submission to initial decision + 4 weeks from acceptance to publication TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3 CD127 Laurye Van Maele, Christophe Carnoy, Delphine Cayet, Pascal Songhet, Laure Dumoutier, Isabel Ferrero, Laure Janot, François Erard, Julie Bertout, Hélène Leger, Florent Sebbane, Arndt Benecke, Jean-Christophe Renauld, Wolf-Dietrich Hardt, Bernhard Ryffel and Jean-Claude Sirard http://www.jimmunol.org/content/early/2010/06/21/jimmun ol.1000115 J Immunol Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2010/06/21/jimmunol.100011 5.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 26, 2021. Published June 21, 2010, doi:10.4049/jimmunol.1000115 The Journal of Immunology TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3negCD127+ Immune Cells in Spleen and Mucosa Laurye Van Maele,*,†,‡,x,{,1 Christophe Carnoy,*,†,‡,x,{,1 Delphine Cayet,*,†,‡,x,{,1 Pascal Songhet,‖ Laure Dumoutier,# Isabel Ferrero,** Laure Janot,††,‡‡ Franc¸ois Erard,††,‡‡ Julie Bertout,{ He´le`ne Leger,x,xx,{{ Florent Sebbane,*,†,‡,x,{ Arndt Benecke,x,xx,{{ Jean-Christophe Renauld,# Wolf-Dietrich Hardt,‖ Bernhard Ryffel,††,‡‡ and Jean-Claude Sirard*,†,‡,x,{ In adaptive immunity, Th17 lymphocytes produce the IL-17 and IL-22 cytokines that stimulate mucosal antimicrobial defenses and tissue repair. In this study, we observed that the TLR5 agonist flagellin induced swift and transient transcription of genes encoding IL-17 and IL-22 in lymphoid, gut, and lung tissues. This innate response also temporarily enhanced the expression of genes Downloaded from associated with the antimicrobial Th17 signature. The source of the Th17-related cytokines was identified as novel populations of CD3negCD127+ immune cells among which CD4-expressing cells resembling lymphoid tissue inducer cells. We also demonstrated that dendritic cells are essential for expression of Th17-related cytokines and so for stimulation of innate cells. These data define that TLR-induced activation of CD3negCD127+ cells and production of Th17-related cytokines may be crucial for the early defenses against pathogen invasion of host tissues. The Journal of Immunology, 2010, 185: 000–000. http://www.jimmunol.org/ oll-like receptors are key players in innate immunity and RecentstudieshighlightedthecontributionofIL-17A,IL-17F,and are essential for sensing microbial components and trigger- IL-22 to defensive reactions within the mucosa (3–6). These cyto- T ing the host defense (1). At the luminal interface, the TLR kines help orchestrate innate immunity by stimulating epithelial response is mediated by the epithelium and mainly consists of neu- cells to produce defense molecules, matrix proteases, and tissue trophil recruitment and activation (2). After microbes cross the ep- repair molecules (7, 8). The source of IL-17A, IL-17F, and IL-22 ithelium, sensing occurs within the lamina propria. However, the varies. During an adaptive response, the lymphocytes that differen- nature of the TLR-mediated innate cells and defense factors that are tiate into Th17 cells are the main producers of cytokines (9). IL-17A triggered by microbial desequestration has yet to be defined. can rapidly be produced during innate responses to bacteria or mi- crobial molecular patterns by gd T lymphocytes in a TLR4- by guest on September 26, 2021 dependent manner, NKT cells activated with a-galactosylceramide, *Institut Pasteur de Lille, Centre d’Infection et d’Immunite´ de Lille; †Institut Na- or lymphoid tissue inducer (LTi)-like cells following stimulation tional de la Sante´ et de la Recherche Me´dicale Unite´ 1019; ‡Centre National de la with the TLR2/Dectin-1 agonist zymosan (10–12). NK-like and Recherche Scientifique Unite´ Mixte de Recherche 8204; xUniversite´ Lille Nord de France; {{Institut de Recherche Interdisciplinaire, Centre National de la Recherche LTi-like innate lymphocytes expressing IL-7Ra, NKp46, the Scientifique Unite´ de Service et de Recherche 3078; {Institut Fe´de´ratif de Recherche transcription factor RORgt, and eventually CCR6 are sources of xx †† 142, Lille; Institut des Hautes E´tudes Scientifiques, Bures-sur-Yvette; University of IL-22 and/or IL-17 in mucosa under steady-state conditions (13– Orle´ans and ‡‡Centre National de la Recherche Scientifique Molecular Immunology and Embryology Unite´ Mixte de Recherche 6218, Institut de Transgenose, Orle´ans, 18). Interestingly, microbial flora-colonizing mucosa are required to ‖ France; Institute of Microbiology, Eidgeno¨ssiche Technische Hochschule Zurich, switch on lasting IL-17 and IL-22 production (15, 17). In absence Zurich; **Ludwig Institute for Cancer Research, Lausanne Branch, University of of these innate lymphocytes, infectious colitis is exacerbated, sug- Lausanne, Epalinges, Switzerland; and #Ludwig Institute for Cancer Research, Brussels Branch, de Duve Institute, Universite´ catholique de Louvain, Brussels, gesting an operational role of IL-22 and IL-17 in the gut’s innate Belgium immunity (15, 17). However, the link between TLR-mediated sig- 1L.V.M., C.C., and D.C. contributed equally to this work. naling, Th17-related cytokine production by innate immune cells, Received for publication January 15, 2010. Accepted for publication May 11, 2010. and mucosal defenses has not been defined. This work was supported by the Institut National de la Sante´ et de la Recherche The ability of TLR5 signaling to induce mucosal production of Me´dicale (to. C.C., L.V.M., D.C., and J.-C.S.), the Institut Pasteur de Lille, the IL-17 and IL-22 and thereby promote antimicrobial defense has Universite´ Lille Nord de France, and the Re´gion Nord Pas de Calais (ARCir Europe). W.-D.H. and J.-C.S. are funded by the European Community (Grant INCO-CT-2006- never been investigated. TLR5 detects flagellins—the main pro- 032296). tein of bacterial flagella (19). Flagellins are expressed by bacteria, Microarray data were deposited in the publicly available database (http://mace.ihes. particularly pathogenic bacteria, in the gut and the lung and acti- fr) with accession number 2844328654. vate epithelial TLR5 signaling (19–21). Flagellin expression is Address correspondence and reprint requests to Dr. Jean-Claude Sirard, Center for switched off as soon as bacteria translocate into the lamina propria Infection and Immunity of Lille, Institut National de la Sante´ et de la Recherche (22). Detection of flagellin molecules represents therefore an Me´dicale Unite´ 1019, Centre National de la Recherche Scientifique Unite´ Mixte de Recherche 8204, Institut Pasteur de Lille, 1, rue du Professeur Calmette, 59019 Lille alarm signal for subepithelial invasion and/or disruption of the Cedex, France. E-mail address: [email protected] epithelial barrier function. TLR5 signaling is rapidly induced in The online version of this article contains supplemental material. the lamina propria dendritic cells (DCs) of the small intestine (23). Abbreviations used in this paper: Ct, cycle threshold; DC, dendritic cell; DTX, diph- In the current study, we show that flagellin activates (via DCs) the theria toxin; gc, common g-chain; LTi, lymphoid tissue inducer; ns, nonsignificant; splenic and mucosal production of IL-17 and IL-22 and the sub- WT, wild-type. sequent expression of target genes. This TLR5-mediated response Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 was associated with a unique population of immune cells express- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000115 2 TLR-MEDIATED INNATE IMMUNE CELL ACTIVATION ing CD127 but not CD3 that resembles LTi cells, LTi-like, or NK- Microarrays neg + like innate lymphocytes. Our findings suggest that CD3 CD127 Total RNA (2 mg) was processed on the Mouse Whole Genome Arrays innate immune cells may be instrumental to the host’s mucosal version 2.0 (Applied Biosystems) (27). Data were analyzed using the defense through the early production of Th17-related cytokines. NeONORM method, and heat maps were created as described previously (27, 28). Gene Ontology was analyzed using the Panther Protein Classi- Materials and Methods fication System (www.pantherdb.org). Mice Statistical analysis Specific pathogen-free mouse strains C57BL/6J, C57BL/6J-Ly5.1, BALB/ The Mann-Whitney U test and the Graphpad Prism software 5.0 were used 2 2 2 2 2 2 2 2 2 2 2 2 c, and Tcrb / , Tcrd / , Tcrb / Tcrd / , Tlr5 / (24); Myd88 / (25); in analyses. The Limma test with Benjamini-Hochberg false discovery rate transgenic animals for pre-TCRa, Cd11c-DTR-EGFP (Itagx-DTR/EGFP) (FDR) correction was used for high-throughput PCR with TaqMan Low 2 2 2 2 2 2 (26); Rag2 / Il2rg / backcrossed on C57BL/6J mice; Cd1d / Density Arrays.
Load more

Recommended publications
  • Role of Cyclosporine in Gingival Hyperplasia: an in Vitro Study on Gingival Fibroblasts
    International Journal of Molecular Sciences Article Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts 1, , 2, 3 3 Dorina Lauritano * y , Annalisa Palmieri y, Alberta Lucchese , Dario Di Stasio , Giulia Moreo 1 and Francesco Carinci 4 1 Department of Medicine and Surgery, Centre of Neuroscience of Milan, University of Milano-Bicocca, 20126 Milan, Italy; [email protected] 2 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via Belmoro 8, 40126 Bologna, Italy; [email protected] 3 Multidisciplinary Department of Medical and Dental Specialties, University of Campania-Luigi Vanvitelli, 80138 Naples, Italy; [email protected] (A.L.); [email protected] (D.D.S.) 4 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-335-679-0163 These authors contributed equally to this work. y Received: 25 November 2019; Accepted: 13 January 2020; Published: 16 January 2020 Abstract: Background: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. Materials and methods: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control.
    [Show full text]
  • Mouse Mxra8 Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Mxra8 Knockout Project (CRISPR/Cas9) Objective: To create a Mxra8 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Mxra8 gene (NCBI Reference Sequence: NM_024263 ; Ensembl: ENSMUSG00000029070 ) is located on Mouse chromosome 4. 10 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 10 (Transcript: ENSMUST00000030947). Exon 1~10 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Phenotypic analysis of mice homozygous for a gene trap allele indicates this mutation has no notable phenotype in any parameter tested in a high-throughput screen. Exon 1 starts from about 0.08% of the coding region. Exon 1~10 covers 100.0% of the coding region. The size of effective KO region: ~3486 bp. The KO region does not have any other known gene. Page 1 of 9 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 3 4 5 6 7 8 9 10 Legends Exon of mouse Mxra8 Knockout region Page 2 of 9 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of start codon is aligned with itself to determine if there are tandem repeats. No significant tandem repeat is found in the dot plot matrix. So this region is suitable for PCR screening or sequencing analysis.
    [Show full text]
  • In Silico Prediction of High-Resolution Hi-C Interaction Matrices
    ARTICLE https://doi.org/10.1038/s41467-019-13423-8 OPEN In silico prediction of high-resolution Hi-C interaction matrices Shilu Zhang1, Deborah Chasman 1, Sara Knaack1 & Sushmita Roy1,2* The three-dimensional (3D) organization of the genome plays an important role in gene regulation bringing distal sequence elements in 3D proximity to genes hundreds of kilobases away. Hi-C is a powerful genome-wide technique to study 3D genome organization. Owing to 1234567890():,; experimental costs, high resolution Hi-C datasets are limited to a few cell lines. Computa- tional prediction of Hi-C counts can offer a scalable and inexpensive approach to examine 3D genome organization across multiple cellular contexts. Here we present HiC-Reg, an approach to predict contact counts from one-dimensional regulatory signals. HiC-Reg pre- dictions identify topologically associating domains and significant interactions that are enri- ched for CCCTC-binding factor (CTCF) bidirectional motifs and interactions identified from complementary sources. CTCF and chromatin marks, especially repressive and elongation marks, are most important for HiC-Reg’s predictive performance. Taken together, HiC-Reg provides a powerful framework to generate high-resolution profiles of contact counts that can be used to study individual locus level interactions and higher-order organizational units of the genome. 1 Wisconsin Institute for Discovery, 330 North Orchard Street, Madison, WI 53715, USA. 2 Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53715, USA. *email: [email protected] NATURE COMMUNICATIONS | (2019) 10:5449 | https://doi.org/10.1038/s41467-019-13423-8 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13423-8 he three-dimensional (3D) organization of the genome has Results Temerged as an important component of the gene regulation HiC-Reg for predicting contact count using Random Forests.
    [Show full text]
  • Enzymatic Encoding Methods for Efficient Synthesis Of
    (19) TZZ__T (11) EP 1 957 644 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/10 (2006.01) C12Q 1/68 (2006.01) 01.12.2010 Bulletin 2010/48 C40B 40/06 (2006.01) C40B 50/06 (2006.01) (21) Application number: 06818144.5 (86) International application number: PCT/DK2006/000685 (22) Date of filing: 01.12.2006 (87) International publication number: WO 2007/062664 (07.06.2007 Gazette 2007/23) (54) ENZYMATIC ENCODING METHODS FOR EFFICIENT SYNTHESIS OF LARGE LIBRARIES ENZYMVERMITTELNDE KODIERUNGSMETHODEN FÜR EINE EFFIZIENTE SYNTHESE VON GROSSEN BIBLIOTHEKEN PROCEDES DE CODAGE ENZYMATIQUE DESTINES A LA SYNTHESE EFFICACE DE BIBLIOTHEQUES IMPORTANTES (84) Designated Contracting States: • GOLDBECH, Anne AT BE BG CH CY CZ DE DK EE ES FI FR GB GR DK-2200 Copenhagen N (DK) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • DE LEON, Daen SK TR DK-2300 Copenhagen S (DK) Designated Extension States: • KALDOR, Ditte Kievsmose AL BA HR MK RS DK-2880 Bagsvaerd (DK) • SLØK, Frank Abilgaard (30) Priority: 01.12.2005 DK 200501704 DK-3450 Allerød (DK) 02.12.2005 US 741490 P • HUSEMOEN, Birgitte Nystrup DK-2500 Valby (DK) (43) Date of publication of application: • DOLBERG, Johannes 20.08.2008 Bulletin 2008/34 DK-1674 Copenhagen V (DK) • JENSEN, Kim Birkebæk (73) Proprietor: Nuevolution A/S DK-2610 Rødovre (DK) 2100 Copenhagen 0 (DK) • PETERSEN, Lene DK-2100 Copenhagen Ø (DK) (72) Inventors: • NØRREGAARD-MADSEN, Mads • FRANCH, Thomas DK-3460 Birkerød (DK) DK-3070 Snekkersten (DK) • GODSKESEN,
    [Show full text]
  • A Systematic Review on the Implications of O-Linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis
    cells Review A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis 1, 1, 1 1,2,3, Rohitesh Gupta y, Frank Leon y, Sanchita Rauth , Surinder K. Batra * and Moorthy P. Ponnusamy 1,2,* 1 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA; [email protected] (R.G.); [email protected] (F.L.); [email protected] (S.R.) 2 Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 681980-5900, USA 3 Department of Pathology and Microbiology, UNMC, Omaha, NE 68198-5900, USA * Correspondence: [email protected] (S.K.B.); [email protected] (M.P.P.); Tel.: +402-559-5455 (S.K.B.); +402-559-1170 (M.P.P.); Fax: +402-559-6650 (S.K.B. & M.P.P.) Equal contribution. y Received: 21 January 2020; Accepted: 12 February 2020; Published: 14 February 2020 Abstract: Glycosylation is the most commonly occurring post-translational modifications, and is believed to modify over 50% of all proteins. The process of glycan modification is directed by different glycosyltransferases, depending on the cell in which it is expressed. These small carbohydrate molecules consist of multiple glycan families that facilitate cell–cell interactions, protein interactions, and downstream signaling. An alteration of several types of O-glycan core structures have been implicated in multiple cancers, largely due to differential glycosyltransferase expression or activity. Consequently, aberrant O-linked glycosylation has been extensively demonstrated to affect biological function and protein integrity that directly result in cancer growth and progression of several diseases.
    [Show full text]
  • Environmental Influences on Endothelial Gene Expression
    ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community.
    [Show full text]
  • 2335 Roles of Molecules Involved in Epithelial/Mesenchymal Transition
    [Frontiers in Bioscience 13, 2335-2355, January 1, 2008] Roles of molecules involved in epithelial/mesenchymal transition during angiogenesis Giulio Ghersi Dipartimento di Biologia Cellulare e dello Sviluppo, Universita di Palermo, Italy TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Extracellular matrix 3.1. ECM and integrins 3.2. Basal lamina components 4. Cadherins. 4.1. Cadherins in angiogenesis 5. Integrins. 5.1. Integrins in angiogenesis 6. Focal adhesion molecules 7. Proteolytic enzymes 7.1. Proteolytic enzymes inhibitors 7.2. Proteolytic enzymes in angiogenesis 8. Perspective 9. Acknowledgements 10. References 1.ABSTRACT 2. INTRODUCTION Formation of vessels requires “epithelial- Growth of new blood vessels (angiogenesis) mesenchymal” transition of endothelial cells, with several plays a key role in several physiological processes, such modifications at the level of endothelial cell plasma as vascular remodeling during embryogenesis and membranes. These processes are associated with wound healing tissue repair in the adult; as well as redistribution of cell-cell and cell-substrate adhesion pathological processes, including rheumatoid arthritis, molecules, cross talk between external ECM and internal diabetic retinopathy, psoriasis, hemangiomas, and cytoskeleton through focal adhesion molecules and the cancer (1). Vessel formation entails the “epithelial- expression of several proteolytic enzymes, including matrix mesenchymal” transition of endothelial cells (ECs) “in metalloproteases and serine proteases. These enzymes with vivo”; a similar phenotypic exchange can be induced “in their degradative action on ECM components, generate vitro” by growing ECs to low cell density, or in “wound molecules acting as activators and/or inhibitors of healing” experiments or perturbing cell adhesion and angiogenesis. The purpose of this review is to provide an associated molecule functions.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • 1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
    Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN.
    [Show full text]
  • Comparative Transcriptome Analysis of Embryo Invasion in the Mink Uterus
    Placenta 75 (2019) 16–22 Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta Comparative transcriptome analysis of embryo invasion in the mink uterus T ∗ Xinyan Caoa,b, , Chao Xua,b, Yufei Zhanga,b, Haijun Weia,b, Yong Liuc, Junguo Caoa,b, Weigang Zhaoa,b, Kun Baoa,b, Qiong Wua,b a Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China b State Key Laboratory for Molecular Biology of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Changchun, China c Key Laboratory of Embryo Development and Reproductive Regulation of Anhui Province, College of Biological and Food Engineering, Fuyang Teachers College, Fuyang, China ABSTRACT Introduction: In mink, as many as 65% of embryos die during gestation. The causes and the mechanisms of embryonic mortality remain unclear. The purpose of our study was to examine global gene expression changes during embryo invasion in mink, and thereby to identify potential signaling pathways involved in implantation failure and early pregnancy loss. Methods: Illumina's next-generation sequencing technology (RNA-Seq) was used to analyze the differentially expressed genes (DEGs) in implantation (IMs) and inter- implantation sites (inter-IMs) of uterine tissue. Results: We identified a total of 606 DEGs, including 420 up- and 186 down-regulated genes in IMs compared to inter-IMs. Gene annotation analysis indicated multiple biological pathways to be significantly enriched for DEGs, including immune response, ECM complex, cytokine activity, chemokine activity andprotein binding. The KEGG pathway including cytokine-cytokine receptor interaction, Jak-STAT, TNF and the chemokine signaling pathway were the most enriched.
    [Show full text]
  • Renal Cell Neoplasms Contain Shared Tumor Type–Specific Copy Number Variations
    The American Journal of Pathology, Vol. 180, No. 6, June 2012 Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2012.01.044 Tumorigenesis and Neoplastic Progression Renal Cell Neoplasms Contain Shared Tumor Type–Specific Copy Number Variations John M. Krill-Burger,* Maureen A. Lyons,*† The annual incidence of renal cell carcinoma (RCC) has Lori A. Kelly,*† Christin M. Sciulli,*† increased steadily in the United States for the past three Patricia Petrosko,*† Uma R. Chandran,†‡ decades, with approximately 58,000 new cases diag- 1,2 Michael D. Kubal,§ Sheldon I. Bastacky,*† nosed in 2010, representing 3% of all malignancies. Anil V. Parwani,*†‡ Rajiv Dhir,*†‡ and Treatment of RCC is complicated by the fact that it is not a single disease but composes multiple tumor types with William A. LaFramboise*†‡ different morphological characteristics, clinical courses, From the Departments of Pathology* and Biomedical and outcomes (ie, clear-cell carcinoma, 82% of RCC ‡ Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania; cases; type 1 or 2 papillary tumors, 11% of RCC cases; † the University of Pittsburgh Cancer Institute, Pittsburgh, chromophobe tumors, 5% of RCC cases; and collecting § Pennsylvania; and Life Technologies, Carlsbad, California duct carcinoma, approximately 1% of RCC cases).2,3 Benign renal neoplasms are subdivided into papillary adenoma, renal oncocytoma, and metanephric ade- Copy number variant (CNV) analysis was performed on noma.2,3 Treatment of RCC often involves surgical resec- renal cell carcinoma (RCC) specimens (chromophobe, tion of a large renal tissue component or removal of the clear cell, oncocytoma, papillary type 1, and papillary entire affected kidney because of the relatively large size of type 2) using high-resolution arrays (1.85 million renal tumors on discovery and the availability of a life-sus- probes).
    [Show full text]
  • ADAMTS13 and 15 Are Not Regulated by the Full Length and N‑Terminal Domain Forms of TIMP‑1, ‑2, ‑3 and ‑4
    BIOMEDICAL REPORTS 4: 73-78, 2016 ADAMTS13 and 15 are not regulated by the full length and N‑terminal domain forms of TIMP‑1, ‑2, ‑3 and ‑4 CENQI GUO, ANASTASIA TSIGKOU and MENG HUEE LEE Department of Biological Sciences, Xian Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, P.R. China Received June 29, 2015; Accepted July 15, 2015 DOI: 10.3892/br.2015.535 Abstract. A disintegrin and metalloproteinase with thom- proteolysis activities associated with arthritis, morphogenesis, bospondin motifs (ADAMTS) 13 and 15 are secreted zinc angiogenesis and even ovulation [as reviewed previously (1,2)]. proteinases involved in the turnover of von Willebrand factor Also known as the VWF-cleaving protease, ADAMTS13 and cancer suppression. In the present study, ADAMTS13 is noted for its ability in cleaving and reducing the size of the and 15 were subjected to inhibition studies with the full-length ultra-large (UL) form of the VWF. Reduction in ADAMTS13 and N-terminal domain forms of tissue inhibitor of metallo- activity from either hereditary or acquired deficiency causes proteinases (TIMPs)-1 to -4. TIMPs have no ability to inhibit accumulation of UL-VWF multimers, platelet aggregation and the ADAMTS proteinases in the full-length or N-terminal arterial thrombosis that leads to fatal thrombotic thrombocy- domain form. While ADAMTS13 is also not sensitive to the topenic purpura [as reviewed previously (1,3)]. By contrast, hydroxamate inhibitors, batimastat and ilomastat, ADAMTS15 ADAMTS15 is a potential tumor suppressor. Only a limited app can be effectively inhibited by batimastat (Ki 299 nM). In number of in-depth investigations have been carried out on the conclusion, the present results indicate that TIMPs are not the enzyme; however, expression and profiling studies have shown regulators of these two ADAMTS proteinases.
    [Show full text]