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Apoptotic and Inflammatory Signalling Pathways in Dendritic Cells

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Apoptotic and inflammatory signalling pathways in dendritic cells Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) genehmigt durch die Fakultät für Naturwissenschaften der Otto-von-Guericke-Universität Magdeburg von Diplom Biologin Beate Fraust geb. Kellert geb. am 15.06.1980 in Frankfurt / Oder Gutachter: Prof. Dr. Ingo Schmitz Prof. Dr. Henning Walczak Eingereicht am: 27.05.2019 Verteidigt am: 30.01.2020 2 Summary Summary The immune system recognizes and eliminates infiltrating microorganisms and other pathogens like viruses and parasites. Beside monocytes, macrophages and B- lymphocytes, dendritic cells (DC) belong to the antigen-presenting cells (APC) and serve as point of intersection between the innate and adaptive immune system. DC recognition of pathogen-associated molecular patterns (PAMPs) and danger- associated molecular patterns (DAMPs) by specific PAMP recognition receptors (PRRs) leads to their maturation and an upregulation of different molecules, e.g. the inflammatory cytokine IL-1β and the anti-apoptotic molecule cFLIP (cellular-FLICE inhibitory protein). The aim of this thesis was the detailed characterisation of the respective inflammatory and apoptotic signalling pathways in murine DCs also by interference via either dominant-negative protein expression or siRNA-mediated knockdown and the analysis of their impact on T cell priming. Beside DC-maturation, lipopolysaccharide, lipoteichonic acid, hyaluronic acid or a cocktail containing TNF-α, IL-4, CD40L and PGE2 together led to an activation of the inflammasome. The mRNA expression of IL-18, IL-33 and IL-1β and the protein expression of the inflammatory caspase-11 increased and IL-18 and IL-1β were secreted. The IL-1β secretion could be further increased by supplemental stimulation with the DAMP ATP, was dependent on caspase-activation as well as potassium gradient and regulated via the P2X7 receptor. DC inflammasome activation did not influence the CD4+ TC proliferation rate, but showed a complex spectrum of induced cytokines, namely TNF-α, IL-2, IL-4, IL-10, GM-CSF, IL-6, IL-5, M-CSF and IL-17 arguing for a complex immune response dependent on the infection background. Expression of a dominant-negative variant of the adapter molecule ASC (dnASC) to block the inflammasome-mediated signalling cascade led to a massive DC death, and did not allow conclusions about the role of inflammatory caspases and their intracellular network in respect to the inflammatory cytokines. DC maturation-induced upregulation of cFLIP inhibited CD95L-induced apoptosis by blocking caspase-8 at the death inducing signalling complex (DISC). A complete genetic knockout of cFLIP in DCs led to a severe spontaneous cell death rescued by expression of one cFLIP-allele. A knockdown of cFLIP also directly diminished DC lifespan, but had no specific influence on TC proliferation rate and DC survival during DC-TC interaction. These findings provide new insights in the fundamental roles of ASC and cFLIP for the lifespan of DCs and may help to further develop the DC-based immunotherapy. 3 Zusammenfassung Zusammenfassung Das Immunsystem erkennt und eliminiert eindringende Mikroorganismen und andere Pathogene wie Viren und Parasiten. Dendritische Zellen (DZ) zählen neben Monozyten, Makrophagen und B-Lymphozyten zu den professionellen Antigen- präsentierenden Zellen (APC) und fungieren als Schnittstelle zwischen dem angeborenen und dem erworbenen Immunsystem. Das Erkennen fremder molekularer Muster unterschiedlicher Pathogene (pathogen-associated molecular patterns, PAMPs) und eigener Gefahr-assoziierter Muster (danger-associated molecular patterns, DAMPs) über spezifische Rezeptoren (PAMP recognition receptors (PRRs)) führt bei DZ zur Reifung und einer Hochregulation verschiedener Moleküle, wie z.B. dem inflammatorischen Zytokin IL-1β und dem anti-apoptotischen cFLIP (cellular-FLICE inhibitory protein). Das Ziel der Dissertation ist die detaillierte Charakterisierung der zugehörigen inflammatorischen und apototischen Signalwege in murinen DZ, des Weiteren auch durch Interferenz mittels dominant-negativer Proteinexpression bzw. siRNA- vermitteltem Knockdown und deren Auswirkungen auf das T-Zell-Priming. Neben einer DZ-Reifung führen Lipopolysaccharid, Lipoteichonsäure, Hyaluronsäure oder ein Cocktail aus TNF-α, IL-4, CD40L und PGE2 zur Aktivierung des Inflammasoms. Dies führt zu einer gesteigerten Genexpression von IL-18, IL-33 und IL-1β und erhöhter Proteinexpression der inflammatorischen Caspase-11 und zur Freisetzung von IL-18 und IL-1β. Die IL-1β Freisetzung konnte über eine zusätzliche Stimulation mit dem DAMP ATP erhöht werden, war abhängig von der Caspase-Aktivität und einem Kaliumgradienten, und über den P2X7 Rezeptor reguliert. Die Aktivierung des Inflammasoms in DZ hatte keinen Einfluss auf die CD4+ T-Zell-Proliferationsrate, zeigte aber ein komplexes Spektrum induzierter Zytokine, wie TNF-α, IL-2, IL-4, IL-10, GM-CSF, IL-6, IL-5, M-CSF und IL-17, welches für eine komplexe Immunantwort in Abhängigkeit vom Infektionshintergrund spricht. Die Expression einer dominant-negativen Form des Adaptermoleküls ASC (dnASC), welche den inflammatorischen Signalweg blockieren sollte, führte zu einem massiven DZ-Sterben und ließ keine Rückschlüsse über die Rolle der inflammatorischen Caspasen und ihr intrazelluläres Netzwerk im Hinblick auf die inflammatorischen Zytokine zu. Die durch DZ-Reifung induzierte Hochregulation des Apoptose-Inhibitors cFLIP führt zu einer Resistenz gegenüber der CD95L-induzierten Apoptose durch die Inhibition der Caspase-8 im CD95 Rezeptorkomplex (DISC). Ein kompletter genetischer Verlust von cFLIP führte zu einem spontanen DZ-Zelltod, welcher bereits durch das Vorhandensein eines cFLIP-Allels verhindert werden konnte. Eine Verringerung der cFLIP Expression in DZ führte ebenso zu einer Verkürzung ihrer Lebensdauer, zeigte aber keinen spezifischen Einfluss auf die TZ-Proliferationsrate und das Überleben der DZ im Interaktionsmodell. 4 Zusammenfassung Diese Befunde erlauben einen tieferen Einblick in die fundamentalen Rollen von ASC und cFLIP in dendritischen Zellen und helfen möglicherweise bei der Weiterentwicklung der DZ-basierten Immuntherapie. 5 Content Content Summary 3 Zusammenfassung 4 Content 6 1. Introduction 11 1.1. The immune system 11 1.1.1. Physiological function of the immune system .............................................. 11 1.1.2. Function of dendritic cells ............................................................................ 12 1.1.3. The inflammasome ...................................................................................... 18 1.1.4. Processing and function of IL-1β, IL-18 and IL-33 ....................................... 21 1.1.5. Inhibition of the inflammasome by pathogens ............................................. 25 1.1.6. The role of the inflammasome in DCs ......................................................... 27 1.2. Role of cell death for regulation of DC immune response 28 1.2.1. The different faces of cell death................................................................... 28 1.2.2. The intrinsic cell death pathway................................................................... 29 1.2.3. CD95L-mediated apoptosis as an extrinsic cell death pathway ................... 30 1.2.4. Inhibition of CD95-mediated apoptosis by cFLIP ......................................... 32 1.2.5. Apoptosis in dendritic cells .......................................................................... 35 1.3. Aims 38 2. Material and Methods 40 2.1. Material 40 2.1.1. Chemicals .................................................................................................... 40 2.1.2. Enzymes and molecular biology reagents ...................................................... 41 2.1.3. Ready-made reaction systems (Kits) .............................................................. 42 2.1.4. Phosphatase and protease inhibitors.............................................................. 42 6 Content 2.1.5. Pharmacological stimulating substances ........................................................ 43 2.1.6. Stimulating Cytokines ..................................................................................... 43 2.1.7. Molecular weight markers ............................................................................... 44 2.1.8. Protein molecular weight markers................................................................... 44 2.1.9. Table 2: Primary antibodies for Western blot analysis .................................... 44 2.1.10. Table 3: Antibodies for FACS analysis ......................................................... 45 2.1.11. Vector backbones ......................................................................................... 46 2.1.12. Prokaryotic cells............................................................................................ 47 2.1.13. Eukaryotic cells ............................................................................................. 47 2.1.14. Animals ......................................................................................................... 48 2.1.15. Culture media for bacterial cells ................................................................... 48 2.1.16. Cell culture media and reagents for cells ...................................................... 49 2.1.17. Generally used buffers .................................................................................. 49 2.1.18. Buffer and reagents for protein
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