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NLRP3 Protects the Alveolar Barrier by an Inflammasome-Independent Increase of Epithelial Cell Adherence

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NLRP3 Protects the Alveolar Barrier by an Inflammasome-Independent Increase of Epithelial Cell Adherence NLRP3 protects the alveolar barrier by an inflammasome-independent increase of epithelial cell adherence Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Elena Ivaylova Kostadinova, Msc Place of Birth: Sofia, Bulgaria Berlin 2017 1 Time period: 01.11.2011 – 31.08.2016 Supervisor: Prof. Dr. Bastian Opitz Institute: Medizinische Klinik m.S. Infektiologie und Pneumologie Charitѐ-Universitätsmedizin, Berlin 1st Reviewer: Prof. Dr. Bastian Opitz Medizinische Klinik m.S. Infektiologie und Pneumologie Charitѐ-Universitätsmedizin, Berlin 2nd Reviewer: Prof. Dr. Rupert Mutzel Institut für Biologie - Microbiologie Freie Universität, Berlin Date of defence: 19.06.2017 2 3 ACKNOWLEDGEMENTS First of all, I want to express my gratitude to my supervisor Prof. Bastian Opitz for giving me the opportunity to work on this fascinating project in such a stimulating environment. Moreover, I am very grateful to Prof. Rupert Mutzel for accepting to be my second referee. I would also like to thank Prof. Martin Witzenrath and Dr. Birgitt Gutbier for all their support and valuable advice throughout this work and Prof. Norbert Suttorp for giving me the chance to perform my PhD in the Department of Infectious Diseases and Pulmonary Medicine. Furthermore, I am thankful to the International Max Planck Research School for Infectious Diseases and Immunology as part of the ZIBI graduate school for funding me and enabling me to attend numerous lectures, seminars and international conferences. I also would like to thank the former and current coordinators Dr. Susanne Beetz, Dr. Martina Sick, Dr. Andreas Schmidt and Dr. Juliane Kofer, as well as my colleagues and friends from the ZIBI Graduate School. I am particularly grateful to Dr. Catherine Chaput who always motivated me in the hard times and worked by my side no matter what. I also thank Dr. Juliane Lippmann who supported me with the final parts of my project and Dr. Thomas Korte for his technical assistance. Moreover, I would like to thank Prof. Dr. Leif Sander and Dr. Janine Zahlten for their readiness to help in every situation. I am also grateful to all the current and former members of the Opitz lab for being there for me and for providing a friendly atmosphere inside and outside the lab: Anne, Claudia, Jan, Juan, Laura, Oliver, Philip, Sandra, Uwe. Also, many special thanks to all current and alumni members of the DDDC, to my other colleagues from the Department of Infectious Diseases and Pulmonary Medicine and especially to my Matteo. Finally, I would like to express my enormous gratitude to the most amazing family in the world, Glúmur and my awesome friends in Berlin and all over the world for their support and encouragement during the past years. Thank you for your endless love, trust and support. I am nothing without you and I owe it all to you. 4 5 Table of Contents I - Introduction .................................................................................. 10 1. LUNG ALVEOLAR MEMBRANE MAINTENANCE .............................................. 10 2. PNEUMOCOCCAL PNEUMONIA ............................................................................ 13 2.1. Epidemiology of pneumonia and pneumoccocal disease ....................................... 13 2.2. Virulence factors of S. pneumoniae ...................................................................... 15 2.2.1. Pneumolysin (PLY) ................................................................................ 15 2.2.2. Capsule .................................................................................................... 17 2.2.3. Other virulence factors ............................................................................. 17 2.3. Acute respiratory distress synrome (ARDS) ........................................................ 18 3. INNATE IMMUNE SYSTEM ................................................................................... 19 3.1. Interactions with the microbiota .......................................................................... 20 3.2. Pattern recognition receptors (PRRs) .................................................................. 20 3.2.1. Toll-like receptors (TLRs) ........................................................................ 21 3.2.2. C-type lectin receptors (CTLs) .................................................................. 22 3.2.3. RIG-I-like receptors (RLRs) ................................................................... 22 3.2.4. Cytosolic DNA sensors ............................................................................. 23 3.2.5. NOD-like receptors (NLRs) ..................................................................... 23 3.2.5.1. NOD1 and NOD2 .............................................................................. 24 3.2.5.2. NLR and other inflammasomes .......................................................... 25 - NLRP1 inflammasome ................................................................ 27 - NLRC4 inflammasome ................................................................. 28 - AIM2 inflammasome.................................................................... 28 - Pyrin inflammasome .................................................................... 29 4. THE NLRP3 INFLAMMASOME ............................................................................. 30 4.1. NLRP3 priming and pre-activation events ........................................................... 30 4.2. NLRP3 activation ............................................................................................... 32 4.3. The non-canonical inflammasome pathway .......................................................... 35 4.4. NLRP3 regulation ............................................................................................... 35 5. INNATE IMMUNE RECOGNITION OF S. PNEUMONIAE ................................. 37 6. AIM OF THE STUDY .............................................................................................. 39 6 II - Results ................................................................................................ 40 1. Co-housing of Nlrp3-/- and WT animals increases similarity of gut microbiota .......... 40 2. NLRP3 protects the lung barrier function during in vivo pneumococcal infection ...... 43 3. NLRP3 protects the lung barrier during treatment with aerosolized pneumolysin (PLY) in isolated murine lungs .................................................................................. 45 4. NLRP3 enhances lung epithelial but not endothelial barrier function upon PLY treatment .................................................................................................................. 47 5. The protective function of NLRP3 in lung epithelial cells is independent of epithelial caspase-1/11 and cannot be rescued by WT alveolar macrophages ............................. 49 6. NLRP3 protects the lung during S.pneumoniae infection independently of the cytokines IL-1β and IL-18 ......................................................................................... 51 7. The expression of adhesion molecules by alveolar epithelial cells is not affected by NLRP3 ..................................................................................................................... 52 8. NLRP3 facilitates the attachment of alveolar epithelial cells to the extracellular matrix upon PLY treatment ................................................................................................. 54 9. The function of NLRP3 in epithelial barrier maintenance is not due to increased cell death ........................................................................................................................ 57 III – Discussion ................................................................................ 58 1. SUMMARY .............................................................................................................. 58 2. INFLAMMSOMES AND THE MICROBIOTA ........................................................ 59 3. NLRP3-DEPENDENT PROTECTION MECHNISMS IN THE LUNG ................... 61 3.1. The protective function of NLRP3 is independent of ASC, IL-1β and IL-18 ........ 61 3.2. PLY – a central NLRP3 activator ....................................................................... 63 3.3. Epithelial cell-intrinsic NLRP3 mediates barrier function ................................... 64 3.4. Epithelial barrier maintenance mechanisms and the role of NLRP3 .................... 66 3.4.1. The role of junctions ................................................................................ 67 3.4.2. The role of cell death ............................................................................... 68 3.4.3. The role of ions ........................................................................................ 69 3.4.4. The role of the cyoskeleton ...................................................................... 71 4. FUTURE EXPERIMENTS ..................................................................................... 73 5. CONCLUSION ......................................................................................................... 74 7 IV – Materials and Methods ...................................... 76 1. BACTERIAL CULTURE .......................................................................................... 76 2. MICE........................................................................................................................
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