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Chemical Modifications of DNA Activate the Cgas/STING-Signaling Pathway Even in the Presence of the Cytosolic Exonuclease TREX1

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Chemical Modifications of DNA Activate the Cgas/STING-Signaling Pathway Even in the Presence of the Cytosolic Exonuclease TREX1 Chemical modifications of DNA activate the cGAS/STING-signaling pathway even in the presence of the cytosolic exonuclease TREX1 Dissertation zur Erlangung des Doktorgrades (Dr. rer. nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Christina Mertens aus Bergisch-Gladbach Bonn, März 2015 ! Angefertigt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn. 1. Gutachter: Prof. Dr. Gunther Hartmann 2. Gutachter: Prof. Dr. Michael Hoch Tag der Promotion: 12.08.2015 Erscheinungsjahr: 2015 ! ! Die vorliegende Arbeit wurde im Zeitraum von Mai 2011 bis März 2015 am Institut für Klinische Chemie und Klinische Pharmakologie der Rheinischen Friedrich-Wilhelms-Universität Bonn unter Leitung von Prof. Dr. Gunther Hartmann und Betreuung durch Prof. Dr. Winfried Barchet angefertigt. Hiermit erkläre ich an Eides statt, - dass ich die Arbeit ohne fremde Hilfe angefertigt und andere Hilfsmittel als die in der Dissertation angegebenen nicht benutzt habe; insbesondere, dass wörtlich oder sinngemäß aus Veröffentlichungen entnommene Stellen als solche kenntlich gemacht worden sind, - dass ich mich bis zu diesem Tage noch keiner Doktorprüfung unterzogen habe. Ebenso hat die von mir vorgelegte Dissertation noch keiner anderen Fakultät oder einem ihrer Mitglieder vorgelegen, - dass ein Dienststraf- oder Ehrengerichtsverfahren gegen mich weder geschwebt hat noch gegenwärtig schwebt. Bonn, März 2015 (Christina Mertens) ! ! Für meine Familie ! ! Acknowledgement I would like to express my gratitude to Prof. Dr. Gunther Hartmann and the Institute of Clinical Chemistry and Clinical Pharmacology for giving me the possibility to complete this work. Especially, I would like to thank Prof. Dr. Winfried Barchet for his support and supervision throughout my research project. He was significantly involved in the success of my experiments. I would like to thank my reviewers for their efforts reading and examining this work. I know that they are very busy, and thus, I am even more grateful that they could spare a bit of their time for my thesis and me. I am also very grateful to the whole Barchet group, notably to Volker Böhnert, Dr. Nadine Gehrke, Soheila Riemann, Malte Stasch and Dr. Thomas Zillinger, who were always willing to give me any help I needed. Moreover, I would like to thank Dr. Tobias Bald from the Institute of Dermatology for his help with the ear injection experiments. Additionally, I owe my friends a debt of gratitude for encouraging me to continue on with this work and never give up. In particular, I am very much obliged to Christian Pipper who was of great help in difficult times. My family I would like to thank for support in all phases of life. This work is dedicated to you! Last but not least, I would like to thank all who looked closely at the final version of this thesis. Thank you! ! ! Table of contents Summary.....................................................................................................................................1 1. Introduction .............................................................................................................................2 1.1. The Immune System........................................................................................................2 1.2. Pattern Recognition Receptors ........................................................................................3 1.2.1. Immune Sensing Of Nucleic Acids............................................................................3 1.2.1.1. Endosomal Toll-like Receptors ..........................................................................3 1.2.1.2. Cytosolic RNA Sensing By RIG-l-like Receptors ...............................................5 1.2.1.3. Cytosolic DNA Sensing ......................................................................................7 1.3. Type I Interferon System................................................................................................11 1.4. UV Radiation..................................................................................................................12 1.4.1. UV- induced DNA Damage .....................................................................................13 1.4.2. Repair Of UV-induced DNA Damages....................................................................16 1.4.3. UV-induced Apoptosis.............................................................................................16 1.5. Deoxyribonucleases.......................................................................................................17 1.6. Lupus Erythematosus ....................................................................................................17 1.7. Lupus And Neutrophil Extracellular Traps .....................................................................19 1.8. The MRL/lpr Mouse Model.............................................................................................20 1.9. Aim.................................................................................................................................22 2. Material And Methods ...........................................................................................................23 2.1. Materials ........................................................................................................................23 2.1.1. Equipment...............................................................................................................23 2.1.2. Expendable Materials..............................................................................................24 2.1.3. Chemicals ...............................................................................................................24 2.1.4. ELISA ......................................................................................................................25 2.1.5. Transfection Reagents............................................................................................26 2.1.6. Enzymes .................................................................................................................26 2.1.7. Western Blot And FACS Antibodies........................................................................26 2.1.8. Kits ..........................................................................................................................26 2.1.9. MACS Beads From Miltenyi Biotec.........................................................................26 2.1.10. Oligonucleotides....................................................................................................26 2.1.11. Nucleic Acids.........................................................................................................27 2.1.12. Media, Solutions, Substrates And Buffers.............................................................27 2.1.13. Primary Cells And Cell Lines.................................................................................29 2.1.14. Mice.......................................................................................................................29 2. 2. Methods ........................................................................................................................30 2.2.1. Cell Culture .............................................................................................................30 2.2.1.1. General Preconditions......................................................................................30 2.2.1.2. Subculturing Of Cells .......................................................................................30 2.2.1.3. Determination Of The Cell Number..................................................................30 2.2.1.4. Freezing And Thawing Of Cells .......................................................................30 2.2.2. Isolation And Generation Of Cells...........................................................................31 2.2.2.1. Preparation Of Murine Bone Marrow DCs .......................................................31 2.2.2.2. Isolation Of Murine Spleen Cells......................................................................31 2.2.2.3. Isolation Of Human Peripheral Blood Mononuclear Cells ................................31 2.2.2.4. Magnetic-activated Cell Sorting .......................................................................32 2.2.2.5. Isolation Of Human Neutrophils From Fresh Blood .........................................32 2.2.2.6. Isolation Of Murine Neutrophils From Bone Marrow ........................................33 2.2.3. Stimulation And Treatment Of Cells........................................................................33 2.2.3.1. Transfection Of Nucleic Acids ..........................................................................33 2.2.3.2. UV Irradiation Of Cells And DNA .....................................................................33 2.2.3.3. HOCl/ H2O2-treatment Of Cells And DNA ........................................................33 2.2.3.4. Induction Of NETosis .......................................................................................34 2.2.3.5. Incubation Of DNA With Human LL37 Peptide ................................................34 ! ! 2.2.4. Enzyme Linked Immunosorbent Assays.................................................................34 2.2.4.1. Murine IFN-! ELISA.........................................................................................34
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