37 results on '"Valentin Schatz"'
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2. ‘Crawling Jurisdiction’: Revisiting the Scope and Significance of the Definition of Sedentary Species
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Valentin Schatz
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Law - Published
- 2022
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3. Regulating Exceptions for Research and Exploratory Fishing in Southern Ocean Marine Protected Areas: A Comparative Analysis on Balancing Conservation and Commercial Use
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Nengye Liu, Alexander Proelss, and Valentin Schatz
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Political Science and International Relations ,Management, Monitoring, Policy and Law ,Development ,Law - Published
- 2022
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4. The Status of Crimea and the Sea of Azov as a Jurisdictional Hurdle in Ukraine v. Russia
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Valentin Schatz
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History ,Law - Abstract
On 21 February 2020, the arbitral tribunal constituted under Annex vii of the United Nations Convention on the Law of the Sea (unclos) in the Dispute Concerning Coastal State Rights in the Black Sea, Sea of Azov, and Kerch Strait (Ukraine v. the Russian Federation) rendered its award concerning preliminary objections. This comment focuses on the arbitral tribunal’s findings concerning Russia’s two most important and far-reaching objections, both of which concern jurisdiction ratione materiae. First, it argues that the arbitral tribunal convincingly declined jurisdiction over those of Ukraine’s claims, which would have required the arbitral tribunal to decide the dispute between Ukraine and Russia concerning sovereignty over Crimea. Second, this comment analyzes the arbitral tribunal’s conclusion that the parties’ dispute concerning the status of the Sea of Azov and Kerch Strait was not of an exclusively preliminary character and must, therefore, be reserved for the proceedings on the merits.
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- 2021
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5. Macrophages inhibit Coxiella burnetii by the ACOD1 ‐itaconate pathway for containment of Q fever
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Lisa Kohl, Md Nur A Alam Siddique, Barbara Bodendorfer, Raffaela Berger, Annica Preikschat, Christoph Daniel, Martha Ölke, Elisabeth Liebler‐Tenorio, Jan Schulze‐Luehrmann, Michael Mauermeir, Kai‐Ting Yang, Inaya Hayek, Manuela Szperlinski, Jennifer Andrack, Ulrike Schleicher, Aline Bozec, Gerhard Krönke, Peter J Murray, Stefan Wirtz, Masahiro Yamamoto, Valentin Schatz, Jonathan Jantsch, Peter Oefner, Daniel Degrandi, Klaus Pfeffer, Katja Mertens‐Scholz, Simon Rauber, Christian Bogdan, Katja Dettmer, Anja Lührmann, and Roland Lang
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ddc:610 ,610 Medizin ,Molecular Medicine ,Cis-aconitate decarboxylase 1 ,Coxiella burnetii ,Immune responsive gene 1 ,immunometabolism ,itaconate - Abstract
Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis‐aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti‐microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1‐derived itaconate is a key factor in the macrophage‐mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.
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- 2022
6. Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever
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Lisa Kohl, Md. Nur A Alam Siddique, Barbara Bodendorfer, Raffaela Berger, Annica Preikschat, Christoph Daniel, Martha Ölke, Michael Mauermeir, Kai-Ting Yang, Inaya Hayek, Manuela Szperlinski, Jan Schulze-Luehrmann, Ulrike Schleicher, Aline Bozec, Gerhard Krönke, Peter J. Murray, Stefan Wirtz, Masahiro Yamamoto, Valentin Schatz, Jonathan Jantsch, Peter Oefner, Daniel Degrandi, Klaus Pfeffer, Simon Rauber, Christian Bogdan, Katja Dettmer, Anja Lührmann, and Roland Lang
- Abstract
Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis- aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1-/- mice caused increased C. burnetii burden, significant weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1-/- mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1-/-mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.
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- 2022
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7. Book Reviews
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Valentin Schatz
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Law - Abstract
W. A. Schabas, The Trial of the Kaiser, Oxford University Press, Oxford 2018, 432 pages, ISBN 9780198833857. (Prof. J. M. Reijntjes, Prof.em. in Criminal Law, The Open University of the Netherlands and the University of Curaçao.) Harold Hongju Koh, The Trump Administration and International Law, Oxford University Press, Oxford 2018, 232 pages, ISBN 9780190912185. (David l. Sloss, John A. and Elizabeth H. Sutro Professor of Law, Santa Clara University School of Law) Gina Heathcote, Feminist Dialogues on International Law: Success, Tensions, Futures, Oxford University Press, Oxford 2019, 256 pages, ISBN 9780199685103. (Aoife O'Donoghue, Professor of International Law and Governance, Durham University Law School) Steven Wheatley, The Idea of International Human Rights Law, Oxford University Press, New York 2019, 204 pages, ISBN 978-0-19-874984-4. (Mark A. Chinen, Professor of Law at the Seattle University School of Law and a Fellow of the Fred T. Korematsu Center for Law and Equality) Marco Longobardo, The Use of Force in Occupied Territory, Cambridge University Press, Cambridge 2018, xxix+320 pages, ISBN 9781108473415. (Michael Bothe, Professor Emeritus of Public Law, Johann Wolfgang Goethe University, Frankfurt am Main) Shavana Musa, Victim Reparation Under the Ius Post Bellum: An Historical and Normative Perspective, Cambridge University Press, Cambridge 2019, 290 pages, ISBN 9781108471732. (Dr. Jens Iverson, Assistant Professor of Public International Law, Leiden Law School, Leiden University) Russell Buchan, Cyber Espionage and International Law, Hart, Oxford 2019, xxviii+219 pages, ISBN 9781782257363. (François Delerue, Research Fellow in Cyberdefense and International Law, Institut de Recherche stratégique de l'Ecole militaire (IRSEM) and Lecturer, Sciences Po Paris) Alejandro Rodiles, Coalitions of the Willing and International Law: The Interplay Between Formality and Informality, Cambridge University Press, Cambridge 2018, xx+287 pages, ISBN 978-1-10-849365-9. (Matteo Tondini, Legal Advisor and Researcher Member, Italian Group, International Society for Military Law and the Law of War) Cindy Wittke, Law in the Twilight: International Courts and Tribunals, the Security Council and the Internationalisation of Peace Agreements Between State and Non-State Parties, Cambridge University Press, Cambridge 2018, 244 pages, ISBN 9781108335676. (Kimana Zulueta-Fülscher, Head of International IDEA's MyConstitution Programme (Yangon, Myanmar)) P. Chandrasekhara Rao and Philippe Gautier, The International Tribunal for the Law of the Sea: Law, Practice and Procedure, Edward Elgar Publishing, Cheltenham 2018, xxvii+363 pages, ISBN 9781786433008. (Valentin J. Schatz, Research Associate, Chair of International Law of the Sea and International Environmental Law, Public International Law and Public Law (Alexander Proelß), Faculty of Law, University of Hamburg) Lloyd Freeburn, Regulating International Sport. Power, Authority and Legitimacy, Brill/Nijhoff, Leiden 2018, 277 pages, ISBN 978-90-04-37978-7. (Christian J. Tams, Chair of International Law, University of Glasgow; Director, Glasgow Centre of International Law & Security)
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- 2021
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8. Mechanisms controlling bacterial infection in myeloid cells under hypoxic conditions
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Valentin Schatz, Anja Lührmann, Inaya Hayek, Christian Bogdan, and Jonathan Jantsch
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Staphylococcus aureus ,Neutrophils ,Review ,medicine.disease_cause ,Dendritic cells ,Microbiology ,Mycobacterium tuberculosis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Animals ,Humans ,Myeloid Cells ,ddc:610 ,HIF1α ,Hypoxia ,Molecular Biology ,Pathogen ,030304 developmental biology ,Pharmacology ,0303 health sciences ,biology ,Bacteria ,Pseudomonas aeruginosa ,Macrophages ,Cell Biology ,Hypoxia (medical) ,biology.organism_classification ,Coxiella burnetii ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell Hypoxia ,Oxygen ,Metabolism ,Salmonella enterica ,Host-Pathogen Interactions ,Molecular Medicine ,medicine.symptom ,Infection ,030215 immunology - Abstract
Various factors of the tissue microenvironment such as the oxygen concentration influence the host–pathogen interaction. During the past decade, hypoxia-driven signaling via hypoxia-inducible factors (HIF) has emerged as an important factor that affects both the pathogen and the host. In this chapter, we will review the current knowledge of this complex interplay, with a particular emphasis given to the impact of hypoxia and HIF on the inflammatory and antimicrobial activity of myeloid cells, the bacterial responses to hypoxia and the containment of bacterial infections under oxygen-limited conditions. We will also summarize how low oxygen concentrations influence the metabolism of neutrophils, macrophages and dendritic cells. Finally, we will discuss the consequences of hypoxia and HIFα activation for the invading pathogen, with a focus on Pseudomonas aeruginosa, Mycobacterium tuberculosis, Coxiella burnetii, Salmonella enterica and Staphylococcus aureus. This includes a description of the mechanisms and microbial factors, which the pathogens use to sense and react to hypoxic conditions.
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- 2020
9. Acidic Microenvironments Found in Cutaneous
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Linus, Frick, Linda, Hinterland, Kathrin, Renner, Marion, Vogl, Nathalie, Babl, Simon, Heckscher, Anna, Weigert, Susanne, Weiß, Joachim, Gläsner, Raffaela, Berger, Peter J, Oefner, Katja, Dettmer, Marina, Kreutz, Valentin, Schatz, and Jonathan, Jantsch
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Anti-Infective Agents ,Antiparasitic Agents ,Macrophages ,Nitric Oxide ,Leishmania major - Abstract
Local tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous
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- 2021
10. High Na+ Environments Impair Phagocyte Oxidase-Dependent Antibacterial Activity of Neutrophils
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Luka Krampert, Katharina Bauer, Stefan Ebner, Patrick Neubert, Thomas Ossner, Anna Weigert, Valentin Schatz, Martina Toelge, Agnes Schröder, Martin Herrmann, Markus Schnare, Anca Dorhoi, and Jonathan Jantsch
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reactive oxygen species ,neutrophils ,phagocyte oxidase ,Immunologic diseases. Allergy ,RC581-607 ,sodium ,infection - Abstract
Infection and inflammation can augment local Na+ abundance. These increases in local Na+ levels boost proinflammatory and antimicrobial macrophage activity and can favor polarization of T cells towards a proinflammatory Th17 phenotype. Although neutrophils play an important role in fighting intruding invaders, the impact of increased Na+ on the antimicrobial activity of neutrophils remains elusive. Here we show that, in neutrophils, increases in Na+ (high salt, HS) impair the ability of human and murine neutrophils to eliminate Escherichia coli and Staphylococcus aureus. High salt caused reduced spontaneous movement, degranulation and impaired production of reactive oxygen species (ROS) while leaving neutrophil viability unchanged. High salt enhanced the activity of the p38 mitogen-activated protein kinase (p38/MAPK) and increased the interleukin (IL)-8 release in a p38/MAPK-dependent manner. Whereas inhibition of p38/MAPK did not result in improved neutrophil defense, pharmacological blockade of the phagocyte oxidase (PHOX) or its genetic ablation mimicked the impaired antimicrobial activity detected under high salt conditions. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) overcame high salt-induced impairment in ROS production and restored antimicrobial activity of neutrophils. Hence, we conclude that high salt-impaired PHOX activity results in diminished antimicrobial activity. Our findings suggest that increases in local Na+ represent an ionic checkpoint that prevents excessive ROS production of neutrophils, which decreases their antimicrobial potential and could potentially curtail ROS-mediated tissue damage.
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- 2021
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11. Effects of mechanical strain on periodontal ligament fibroblasts in presence of Aggregatibacter actinomycetemcomitans lysate
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Jonathan Jantsch, Agnes Schröder, Julia Stumpf, Eva Paddenberg, Patrick Neubert, Peter Proff, Valentin Schatz, Christian Kirschneck, James Deschner, and Josef Köstler
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Adult ,Tooth Movement Techniques ,Periodontal Ligament ,610 Medizin ,Inflammation ,PDL ,Aggregatibacter actinomycetemcomitans ,Bone remodeling ,Orthodontic tooth movement ,medicine ,Humans ,Periodontal fiber ,Periodontitis ,General Dentistry ,Cells, Cultured ,Dental alveolus ,Periodontal ligament fibroblast, PDL, Orthodontic tooth movement, Periodontitis, Inflammation ,ddc:610 ,biology ,business.industry ,Research ,RK1-715 ,Fibroblasts ,medicine.disease ,biology.organism_classification ,Molecular biology ,RANKL ,Dentistry ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom ,Periodontal ligament fibroblast ,business - Abstract
Purpose Many adult orthodontic patients suffer from periodontitis, which is caused by oral pathogens such as the gram-negative Aggregatibacter actinomycetemcomitans (Agac). Like orthodontic tooth movement, periodontitis is associated with inflammation and alveolar bone remodelling thereby affecting orthodontic treatment. Interactions of both processes, however, are not sufficiently explored, particularly with regard to oxidative stress. Methods After preincubation with Agac lysate for 24 h periodontal ligament fibroblasts (PDLF) were either stretched or compressed for further 48 h simulating orthodontic forces in vitro. We analysed the expression of genes and proteins involved in the formation of reactive oxygen species (NOX-4, ROS) and nitric oxide (NOS-2), inflammation (TNF, IL-6, PTGS-2) and bone remodelling (OPG, RANKL). Results Agac lysate elevated the expression of NOX-4, NOS-2, inflammatory IL-6 and PTGS-2 and the bone-remodelling RANKL/OPG ratio during compressive, but not tensile mechanical strain. Agac lysate stimulated pressure-induced inflammatory signalling, whereas surprisingly ROS formation was reduced. Pressure-induced downregulation of OPG expression was inhibited by Agac lysate. Conclusions Agac lysate impact on the expression of genes and proteins involved in inflammation and bone remodelling as well as ROS formation, when PDLF were subjected to mechanical forces occurring during orthodontic tooth movement.
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- 2021
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12. Simone Vezzani, Jurisdiction in International Fisheries Law: Evolving Trends and New Challenges
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Valentin Schatz
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- 2020
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13. Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis
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Carsten Willam, Valentin Schatz, Gunnar Schley, Nicolai Burzlaff, Kai-Uwe Eckardt, Runolfur Palsson, Alexander Weidemann, Martin Herrmann, Joanna Kalucka, Dörthe M. Katschinski, Jonathan Jantsch, Margarete Goppelt-Struebe, Marleen Mayer, Angelika Beneke, Bernd Klanke, Christoph Daniel, and Margret Thorsteinsdottir
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Male ,0301 basic medicine ,Myeloid ,Anti-Inflammatory Agents ,Glycine ,030232 urology & nephrology ,Renal function ,Mice, Transgenic ,Pharmacology ,Protective Agents ,Prolyl Hydroxylases ,Nephropathy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Basic Helix-Loop-Helix Transcription Factors ,Renal fibrosis ,Animals ,Humans ,Medicine ,Renal Insufficiency, Chronic ,Phagocytes ,business.industry ,Adenine ,Complement C1q ,Prolyl-Hydroxylase Inhibitors ,Mononuclear phagocyte system ,Hypoxia-Inducible Factor 1, alpha Subunit ,Isoquinolines ,medicine.disease ,3. Good health ,Disease Models, Animal ,Kidney Tubules ,030104 developmental biology ,medicine.anatomical_structure ,Hypoxia-inducible factors ,Nephrology ,Nephritis, Interstitial ,Clodronic Acid ,business ,Kidney disease - Abstract
Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.
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- 2019
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14. Mechanical Stress Induce PG-E2 in Murine Synovial Fibroblasts Originating from the Temporomandibular Joint
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Dominique Muschter, Patrick Neubert, Laura Feulner, Peter Proff, Susanne Grässel, Ute Nazet, Valentin Schatz, Jonathan Jantsch, Christian Kirschneck, and Agnes Schröder
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0301 basic medicine ,musculoskeletal diseases ,medicine.medical_specialty ,610 Medizin ,Inflammation ,Osteoarthritis ,Matrix (biology) ,Article ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Synovitis ,Internal medicine ,Hyaluronic acid ,medicine ,Animals ,Receptors, Prostaglandin E ,temporomandibular joint ,lcsh:QH301-705.5 ,ddc:610 ,biology ,Chemistry ,osteoarthritis ,synovitis ,inflammation ,mechanical strain ,030206 dentistry ,General Medicine ,Fibroblasts ,medicine.disease ,Temporomandibular joint ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,lcsh:Biology (General) ,RANKL ,biology.protein ,Stress, Mechanical ,medicine.symptom - Abstract
Genetic predisposition, traumatic events, or excessive mechanical exposure provoke arthritic changes in the temporomandibular joint (TMJ). We analysed the impact of mechanical stress that might be involved in the development and progression of TMJ osteoarthritis (OA) on murine synovial fibroblasts (SFs) of temporomandibular origin. SFs were subjected to different protocols of mechanical stress, either to a high-frequency tensile strain for 4 h or to a tensile strain of varying magnitude for 48 h. The TMJ OA induction was evaluated based on the gene and protein secretion of inflammatory factors (Icam-1, Cxcl-1, Cxcl-2, Il-1ß, Il-1ra, Il-6, Ptgs-2, PG-E2), subchondral bone remodelling (Rankl, Opg), and extracellular matrix components (Col1a2, Has-1, collagen and hyaluronic acid deposition) using RT-qPCR, ELISA, and HPLC. A short high-frequency tensile strain had only minor effects on inflammatory factors and no effects on the subchondral bone remodelling induction or matrix constituent production. A prolonged tensile strain of moderate and advanced magnitude increased the expression of inflammatory factors. An advanced tensile strain enhanced the Ptgs-2 and PG-E2 expression, while the expression of further inflammatory factors were decreased. The tensile strain protocols had no effects on the RANKL/OPG expression, while the advanced tensile strain significantly reduced the deposition of matrix constituent contents of collagen and hyaluronic acid. The data indicates that the application of prolonged advanced mechanical stress on SFs promote PG-E2 protein secretion, while the deposition of extracellular matrix components is decreased.
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- 2021
15. Von 'effective control' zu 'contactless control'?: Die Externalisierung von Migrationskontrolle im zentralen Mittelmeer als Herausforderung für die extraterritoriale Geltung der EMRK
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Valentin Schatz
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- 2021
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16. Differential gene expression response of synovial fibroblasts from temporomandibular joints and knee joints to dynamic tensile stress
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Ute Nazet, Agnes Schröder, Susanne Grässel, Jonathan Jantsch, Christian Kirschneck, Peter Proff, Valentin Schatz, and Patrick Neubert
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0301 basic medicine ,musculoskeletal diseases ,Pathology ,medicine.medical_specialty ,Knee Joint ,610 Medizin ,Gene Expression ,Orthodontics ,Inflammation ,Osteoarthritis ,Bone remodeling ,Extracellular matrix ,Pathogenesis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Synovitis ,medicine ,Animals ,030203 arthritis & rheumatology ,ddc:610 ,Temporomandibular Joint ,business.industry ,Osteoarthritis, Disease induction, Joint diseases, Animal model, Mechanical loading ,Fibroblasts ,medicine.disease ,Temporomandibular joint ,030104 developmental biology ,medicine.anatomical_structure ,Oral Surgery ,medicine.symptom ,business - Abstract
Apart from other risk factors, mechanical stress on joints can promote the development of osteoarthritis (OA), which can also affect the temporomandibular joint (TMJ), resulting in cartilage degeneration and synovitis. Synovial fibroblasts (SF) play an important role in upkeeping joint homeostasis and OA pathogenesis, but mechanical stress as a risk factor might act differently depending on the type of joint. We thus investigated the relative impact of mechanical stress on the gene expression pattern of SF from TMJs and knee joints to provide new insights into OA pathogenesis.Primary SF isolated from TMJs and knee joints of mice were exposed to mechanical strain of varying magnitudes. Thereafter, the expression of marker genes of the extracellular matrix (ECM), inflammation and bone remodelling were analysed by quantitative real-time polymerase chain reaction (RT-qPCR).SF from the knee joints showed increased expression of genes associated with ECM remodelling, inflammation and bone remodelling after mechanical loading, whereas TMJ-derived SF showed reduced expression of genes associated with inflammation and bone remodelling. SF from the TMJ differed from knee-derived SF with regard to expression of ECM, inflammatory and osteoclastogenesis-promoting marker genes during mechanical strain.Osteoarthritis-related ECM remodelling markers experience almost no changes in strain-induced gene expression, whereas inflammation and bone remodelling processes seem to differ depending on synovial fibroblast origin. Our data indicate that risk factors for the development and progression of osteoarthritis such as mechanical overuse have a different pathological impact in the TMJ compared to the knee joint.HINTERGRUND: Mechanische Belastung von Gelenken kann abgesehen von anderen Risikofaktoren die Entwicklung von Osteoarthrose (OA) fördern. Dies kann auch das Kiefergelenk (TMJ) betreffen und zu Knorpeldegeneration und Synovitis führen. Synoviale Fibroblasten (SF) spielen eine wichtige Rolle bei der Aufrechterhaltung der Gelenkhomöostase und bei der OA-Pathogenese, aber je nach Art des Gelenks kann sich mechanische Belastung als Risikofaktor unterschiedlich auswirken. Wir untersuchten daher den relativen Einfluss von mechanischem Stress auf das Genexpressionsmuster von SF aus dem Kiefergelenk und dem Kniegelenk, um neue Erkenntnisse zur OA-Pathogenese zu gewinnen.Aus Kiefer- und Kniegelenken von Mäusen isolierte primäre SF wurden mechanischer Belastung unterschiedlichen Ausmaßes ausgesetzt. Dabei wurde mittels RT-qPCR („quantitative real-time polymerase chain reaction“) die Expression von Markergenen der extrazellulären Matrix (ECM), der Entzündung und des Knochenumbaus analysiert.In SF aus den Kniegelenken war nach mechanischer Belastung die Expression von Genen, welche mit ECM-Umbau, Entzündung und Knochenumbau assoziiert sind, erhöht, während in aus Kiefergelenken isolierten SF die Expression von in Entzündung und Knochenumbauprozesse involvierten Genen reduziert war. Des Weiteren unterschieden sich während der mechanischen Belastung TMJ-SF und Kniegelenk-SF hinsichtlich der Expression von Markergenen für ECM, Entzündung und Förderung der Osteoklastogenese.Osteoarthrosebezogene ECM-Remodellierungsmarker erfahren fast keine Veränderungen in der belastungsinduzierten Genexpression, wohingegen Entzündungs- und Knochenumbauprozesse in Abhängigkeit von der Herkunft der SF unterschiedlich beeinflusst zu sein scheinen. Unsere Daten deuten darauf hin, dass Risikofaktoren für die Entwicklung einer OA und deren Fortschreiten, wie z. B. mechanische Überbeanspruchung, im TMJ einen anderen pathologischen Einfluss haben als im Kniegelenk.
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- 2020
17. Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
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Torben Mentrup, Anna Yamina Stumpff-Niggemann, Nadja Leinung, Christine Schlosser, Katja Schubert, Rebekka Wehner, Antje Tunger, Valentin Schatz, Patrick Neubert, Ann-Christine Gradtke, Janina Wolf, Stefan Rose-John, Paul Saftig, Alexander Dalpke, Jonathan Jantsch, Marc Schmitz, Regina Fluhrer, Ilse D. Jacobsen, and Bernd Schröder
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Multidisciplinary ,Receptors, Pattern Recognition ,Proteolysis ,General Physics and Astronomy ,Lectins, C-Type ,General Chemistry ,ddc:610 ,Ligands ,General Biochemistry, Genetics and Molecular Biology ,Signal Transduction - Abstract
Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal β-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses.
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- 2020
18. Ahabs Erbe
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Valentin Schatz and Tobias Hofmann
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- 2018
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19. NCX1 represents an ionic Na+ sensing mechanism in macrophages
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Patrick Neubert, Arne Homann, David Wendelborn, Anna-Lorena Bär, Luka Krampert, Maximilian Trum, Agnes Schröder, Stefan Ebner, Andrea Weichselbaum, Valentin Schatz, Peter Linz, Roland Veelken, Jonas Schulte-Schrepping, Anna C. Aschenbrenner, Thomas Quast, Christian Kurts, Sabrina Geisberger, Karl Kunzelmann, Karin Hammer, Katrina J. Binger, Jens Titze, Dominik N. Müller, Waldemar Kolanus, Joach
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- 2020
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20. Myeloid Cell–Derived HIF-1α Promotes Control of Leishmania major
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Jonathan Jantsch, Bernhard Brüne, Jennifer M. McNiff, Maximilian J. Waldner, Yannic Strüssmann, Uwe Ritter, Christian Bogdan, Jens Wild, Valentin Schatz, Carsten Willam, Alexander Mahnke, Gunnar Schley, Oscar R. Colegio, and Nathalie Dehne
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Lipopolysaccharides ,0301 basic medicine ,Myeloid ,Immunology ,Cell ,Leishmaniasis, Cutaneous ,Nitric Oxide ,Article ,Parasite Load ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cutaneous leishmaniasis ,medicine ,Animals ,Humans ,Immunology and Allergy ,Myeloid Cells ,Leishmania major ,Skin ,Innate immune system ,biology ,Macrophages ,Hypoxia-Inducible Factor 1, alpha Subunit ,Leishmania ,biology.organism_classification ,medicine.disease ,Immunity, Innate ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Integrin alpha M ,biology.protein ,Nitric Oxide Synthase ,030215 immunology - Abstract
Hypoxia-inducible factor-1α (HIF-1α), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1α expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major–infected C57BL/6 mice exhibited substantial amounts of HIF-1α in acute cutaneous lesions. In vitro, HIF-1α was required for leishmanicidal activity and high-level NO production by IFN-γ/LPS-activated macrophages. Mice deficient for HIF-1α in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b+ cells. Together, these data illustrate that HIF-1α is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.
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- 2016
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21. Elementary immunology: Na+ as a regulator of immunity
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Jens Titze, Patrick Neubert, Matthias Gebhard, Agnes Schröder, Valentin Schatz, Jonathan Jantsch, Dominik N. Müller, Katrina J. Binger, and Friedrich C. Luft
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0301 basic medicine ,T cell ,Skin salt storage ,Regulator ,T cells ,Immune Cell Function ,Inflammation ,Review ,Biology ,Sodium Chloride ,T-Lymphocytes, Regulatory ,Local Na+ availability ,Cutaneous Elimination ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Immunity ,medicine ,Macrophage ,Animals ,Humans ,Pediatrics, Perinatology, and Child Health ,Immune cell function and activation ,Macrophages ,Sodium ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Nephrology ,Pediatrics, Perinatology and Child Health ,Immunology ,medicine.symptom ,030217 neurology & neurosurgery ,Function (biology) - Abstract
The skin can serve as an interstitial Na+ reservoir. Local tissue Na+ accumulation increases with age, inflammation and infection. This increased local Na+ availability favors pro-inflammatory immune cell function and dampens their anti-inflammatory capacity. In this review, we summarize available data on how NaCl affects various immune cells. We particularly focus on how salt promotes pro-inflammatory macrophage and T cell function and simultaneously curtails their regulatory and anti-inflammatory potential. Overall, these findings demonstrate that local Na+ availability is a promising novel regulator of immunity. Hence, the modulation of tissue Na+ levels bears broad therapeutic potential: increasing local Na+ availability may help in treating infections, while lowering tissue Na+ levels may be used to treat, for example, autoimmune and cardiovascular diseases.
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- 2016
22. Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages
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Peter J. Oefner, Katja Dettmer, Inaya Hayek, Valentin Schatz, Katharina Boden, Stefan Wirtz, Jan Schulze-Luehrmann, Fabian Fischer, Jonathan Jantsch, Katharina Sobotta, Lisa Kohl, Anja Lührmann, and Roland Lang
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Adult ,Male ,STAT3 Transcription Factor ,0301 basic medicine ,Citric Acid Cycle ,610 Medizin ,Q fever ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Pathogen ,lcsh:QH301-705.5 ,Cells, Cultured ,ddc:610 ,biology ,Chemistry ,Effector ,Macrophages ,Intracellular parasite ,Middle Aged ,Hypoxia-Inducible Factor 1, alpha Subunit ,Coxiella burnetii ,biology.organism_classification ,medicine.disease ,bacterial infections and mycoses ,Cell Hypoxia ,Mice, Inbred C57BL ,Oxygen ,Citric acid cycle ,030104 developmental biology ,lcsh:Biology (General) ,bacteria ,Female ,Q Fever ,030217 neurology & neurosurgery ,Intracellular - Abstract
Summary: In hypoxic and inflamed tissues, oxygen (O2)-dependent antimicrobial defenses are impaired due to a shortage of O2. To gain insight into the mechanisms that control bacterial infection under hypoxic conditions, we infected macrophages with the obligate intracellular pathogen Coxiella burnetii, the causative agent of Q fever. Our experiments revealed that hypoxia impeded C. burnetii replication in a hypoxia-inducible factor (HIF) 1α-dependent manner. Mechanistically, under hypoxia, HIF1α impaired the activity of STAT3, which in turn reduced the intracellular level of TCA cycle intermediates, including citrate, and impeded C. burnetii replication in macrophages. However, bacterial viability was maintained, allowing the persistence of C. burnetii, which is a prerequisite for the development of chronic Q fever. This knowledge will open future research avenues on the pathogenesis of chronic Q fever. In addition, the regulation of TCA cycle metabolites by HIF1α represents a previously unappreciated mechanism of host defense against intracellular pathogens. : The mechanisms that control bacterial infection under hypoxic conditions are only partially understood. Hayek et al. show that hypoxia-mediated stabilization of HIF1α results in the inhibition of STAT3 activation and the reduction of TCA metabolite levels, including citrate, in macrophages. This prevents C. burnetii replication without reducing bacterial viability. Keywords: Coxiella burnetii, HIF1α, STAT3, citrate, macrophage
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- 2019
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23. HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting
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Patrick Neubert, Jonathan Jantsch, Christoph Brochhausen, Dominik N. Müller, John R. Ferdinand, Karin Hammer, Jens Titze, Ger van Zandbergen, Michaela Simon, Menna R. Clatworthy, Stefan Wagner, Katrina J. Binger, Valentin Schatz, Carmen Reitinger, Roman G. Gerlach, Christian Kurts, Agnes Schröder, Andrea Weichselbaum, Anna-Lorena Bär, Stefan Tomiuk, Kento Kitada, Zeinab Abdullah, Ferdinand, John [0000-0003-0936-0128], Clatworthy, Menna [0000-0002-3340-9828], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Nitric Oxide Synthase Type II ,macrophage ,Cathepsin B ,ATG12 ,03 medical and health sciences ,Mice ,Sequestosome 1 ,Microscopy, Electron, Transmission ,Osmotic Pressure ,Autophagy ,Escherichia coli ,salt ,Animals ,Mannitol ,ddc:610 ,Phosphoglycerate kinase 1 ,education ,Molecular Biology ,Protein kinase B ,Mechanistic target of rapamycin ,sodium ,Oligonucleotide Array Sequence Analysis ,Homeodomain Proteins ,Inflammation ,education.field_of_study ,030102 biochemistry & molecular biology ,biology ,Macrophages ,TOR Serine-Threonine Kinases ,Sodium ,E. coli ,Autophagosomes ,Nitric oxide synthase 2 ,Cell Biology ,BECN1 ,Hydrogen-Ion Concentration ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,030104 developmental biology ,biology.protein ,cell-autonomous immunity ,610 Medizin und Gesundheit ,Lysosomes ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt ,Transcription Factors - Abstract
Infection and inflammation are able to induce diet-independent Na+-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na+-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na+ (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na+-modulated cell autonomous innate immunity. Abbreviations: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H2DCFDA: 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; E. coli: Escherichia coli; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H+-ATPase; WT: wild type
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- 2019
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24. Low-oxygen tensions found inSalmonella-infected gut tissue boostSalmonellareplication in macrophages by impairing antimicrobial activity and augmentingSalmonellavirulence
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Jonas Jennewein, Valentin Schatz, Steffi Walter, Wolf-Dietrich Hardt, Boas Felmy, Michael Hensel, Jasmin Matuszak, Roman G. Gerlach, Monika Nowottny, Gregor Liebsch, Jonathan Jantsch, and Kathrin Gendera
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chemistry.chemical_classification ,Salmonella ,Reactive oxygen species ,NADPH oxidase ,biology ,Phagocyte ,Immunology ,Virulence ,Salmonella infection ,medicine.disease ,medicine.disease_cause ,Microbiology ,Type three secretion system ,Nitric oxide ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Virology ,biology.protein ,medicine - Abstract
In Salmonella infection, the Salmonella pathogenicity island-2 (SPI-2)-encoded type three secretion system (T3SS2) is of key importance for systemic disease and survival in host cells. For instance, in the streptomycin-pretreated mouse model SPI-2-dependent Salmonella replication in lamina propria CD11c(-)CXCR1(-) monocytic phagocytes/macrophages (MΦ) is required for the development of colitis. In addition, containment of intracellular Salmonella in the gut critically depends on the antimicrobial effects of the phagocyte NADPH oxidase (PHOX), and possibly type 2 nitric oxide synthase (NOS2). For both antimicrobial enzyme complexes, oxygen is an essential substrate. However, the amount of available oxygen upon enteroinvasive Salmonella infection in the gut tissue and its impact on Salmonella-MΦ interactions was unknown. Therefore, we measured the gut tissue oxygen levels in a model of Salmonella enterocolitis using luminescence two-dimensional in vivo oxygen imaging. We found that gut tissue oxygen levels dropped from ∼78 Torr (∼11% O2) to values of ∼16 Torr (∼2% O2) during infection. Because in vivo virulence of Salmonella depends on the Salmonella survival in MΦ, Salmonella-MΦ interaction was analysed under such low oxygen values. These experiments revealed an increased intracellular replication and survival of wild-type and t3ss2 non-expressing Salmonella. These findings were paralleled by blunted nitric oxide and reactive oxygen species (ROS) production and reduced Salmonella ROS perception. In addition, hypoxia enhanced SPI-2 transcription and translocation of SPI-2-encoded virulence protein. Neither pharmacological blockade of PHOX and NOS2 nor impairment of T3SS2 virulence function alone mimicked the effect of hypoxia on Salmonella replication under normoxic conditions. However, if t3ss2 non-expressing Salmonella were used, hypoxia did not further enhance Salmonella recovery in a PHOX and NOS2-deficient situation. Hence, these data suggest that hypoxia-induced impairment of antimicrobial activity and Salmonella virulence cooperate to allow for enhanced Salmonella replication in MΦ.
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- 2015
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25. Cutaneous Na+ Storage Strengthens the Antimicrobial Barrier Function of the Skin and Boosts Macrophage-Driven Host Defense
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Valentin Schatz, Stefan Teufel, Jens Titze, Diana Friedrich, Matthias Heinig, Michael Uder, Andreas Maronna, Alexander Cavallaro, Fabian Fischer, Agnes Schröder, Isabel Siegert, Patrick Neubert, Katrina J. Binger, Natalia Rakova, Matthias Gebhardt, Christoph Küper, Christoph W. Kopp, F. X. Beck, Wolfgang Neuhofer, Clemens Neufert, Christian Bogdan, Jonathan Jantsch, Dominik N. Müller, Friedrich C. Luft, Peter Linz, Gerold Schuler, Jean-Pierre David, and David Wendelborn
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Physiology ,Nitric Oxide Synthase Type II ,Leishmaniasis, Cutaneous ,Biology ,Skin infection ,Nitric Oxide ,p38 Mitogen-Activated Protein Kinases ,Article ,Microbiology ,Nitric oxide ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Anti-Infective Agents ,NFAT5 ,medicine ,Animals ,Humans ,Macrophage ,Leishmania major ,Molecular Biology ,Barrier function ,Skin ,030304 developmental biology ,0303 health sciences ,NFATC Transcription Factors ,Macrophages ,Sodium ,Cell Biology ,biology.organism_classification ,medicine.disease ,3. Good health ,Enzyme Activation ,Nitric oxide synthase ,chemistry ,Immunology ,biology.protein ,030217 neurology & neurosurgery - Abstract
Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection.
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- 2015
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26. Ratiometric luminescence 2D in vivo imaging and monitoring of mouse skin oxygenation
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Alexander Mahnke, Julian Hofmann, Florian Brackmann, Valentin Schatz, Otto S. Wolfbeis, Robert J. Meier, Gregor Liebsch, Regina Trollmann, Xu-dong Wang, Christian Bogdan, and Jonathan Jantsch
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Polarographic electrode ,Chemistry ,Analytical chemistry ,Oxygenation ,Atomic and Molecular Physics, and Optics ,Oxygen tension ,Tissue oxygenation ,In vivo ,Mouse skin ,General Materials Science ,Luminescence ,Instrumentation ,Spectroscopy ,Preclinical imaging ,Biomedical engineering - Abstract
Tissue oxygenation plays a critical role in the pathogenesis of various diseases, but non-invasive, robust and user-friendly methods for its measurement in vivo still need to be established. Here, we are presenting an in vivo oxygen-detection system that uses ratiometric luminescence imaging (RLI) as a readout scheme to determine the skin oxygen tension of mouse hind footpads via side-by-side comparison with more established techniques including luminescence-lifetime imaging using planar sensor films and the polarographic electrode as the gold standard. We also demonstrate that this technology allows the detection of changes in mouse skin tissue oxygenation induced by subjecting mice to systemic hypoxia. The data demonstrate oxygen imaging based on RLI to be a most useful tool for reliably and easily analyzing and monitoring skin tissue oxygenation in vivo. This technology will advance our understanding of local regulation of skin tissue oxygenation in various disease conditions.
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- 2017
27. Hypoxia in Leishmania major Skin Lesions Impairs the NO-Dependent Leishmanicidal Activity of Macrophages
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Christian Bogdan, Jonathan Jantsch, Kirstin Castiglione, Alexander Mahnke, Valentin Schatz, Robert J. Meier, Otto S. Wolfbeis, Ulrike Schleicher, and Julian Hofmann
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Atmosphere Exposure Chambers ,Leishmaniasis, Cutaneous ,Nitric Oxide Synthase Type II ,chemistry.chemical_element ,Dermatology ,Nitric Oxide ,Biochemistry ,Parasite load ,Oxygen ,Lesion ,parasitic diseases ,medicine ,Animals ,Leishmania major ,Hypoxia ,Molecular Biology ,Skin ,Mice, Knockout ,Mice, Inbred BALB C ,Arginase ,ATP synthase ,biology ,Macrophages ,Cell Biology ,respiratory system ,Hypoxia (medical) ,biology.organism_classification ,Leishmania ,Molecular biology ,Phenotype ,Mice, Inbred C57BL ,chemistry ,Immunology ,biology.protein ,medicine.symptom - Abstract
Cure of infections with Leishmania major is critically dependent on the ability of macrophages to induce the type 2 nitic oxide (NO) synthase (NOS2) that produces high levels of NO in the presence of ample oxygen. Therefore, we analyzed the oxygen levels found in leishmanial skin lesions and their effect on the NOS2-dependent leishmanicidal activity of macrophages (MΦ). When L. major skin lesions of self-healing C57BL/6 mice reached their maximum size, the infected tissue displayed low oxygen levels ( p O 2 ~21Torr). MΦ activated under these oxygen tensions failed to produce sufficient amounts of NO to clear L. major . Nos2 -deficient and hypoxic wild-type macrophages displayed a similar phenotype. Killing was restored when MΦ were reoxygenated or exposed to a NO donor. The resolution of the lesion in C57BL/6 mice was paralleled by an increase of lesional p O 2 . When mice were kept under normobaric hypoxia, this caused a persistent suppression of the lesional p O 2 and a concurrent increase of the parasite load. In Nos2 -deficient mice, there was no effect of atmospheric hypoxia. Low oxygen levels found at leishmanial skin lesions impaired the NOS2-dependent leishmanicidal activity of MΦ. Hence, tissue oxygenation represents an underestimated local milieu factor that participates in the persistence of Leishmania .
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- 2014
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28. Article 156 . Establishment of the Authority
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Valentin Schatz
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- 2017
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29. Article 160 . Powers and functions
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Valentin Schatz
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- 2017
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30. Article 158 . Organs of the Authority
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Valentin Schatz
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- 2017
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31. Article 159 . Composition, procedure and voting
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Valentin Schatz
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- 2017
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32. Article 157 . Nature and fundamental principles of the Authority
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Valentin Schatz
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- 2017
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33. High salt reduces the activation of IL-4– and IL-13–stimulated macrophages
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Ralf A. Linker, Valentin Schatz, Katrina J. Binger, Arndt Manzel, Norbert Hubner, Florian Lang, Mark D. Wright, Christian Schwartz, Agnes Schroeder, Carola Rintisch, Matthias Gebhardt, Jens Titze, Markus Kleinewietfeld, Matthias Heinig, Jakob Voelkl, Karl F. Hilgers, Jonathan Jantsch, Dominik N. Müller, Wolfgang Neuhofer, David Voehringer, and Ralf Dechend
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medicine.medical_specialty ,Innate immune system ,T cell ,Inflammation ,General Medicine ,Biology ,M2 Macrophage ,Proinflammatory cytokine ,Endocrinology ,medicine.anatomical_structure ,Cardiovascular and Metabolic Diseases ,Internal medicine ,medicine ,medicine.symptom ,Cell activation ,Protein kinase B ,Interleukin 4 ,Research Article - Abstract
A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
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- 2015
34. Electroporation of siRNA into mouse bone marrow-derived macrophages and dendritic cells
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Isabel, Siegert, Valentin, Schatz, Alexander T, Prechtel, Alexander, Steinkasserer, Christian, Bogdan, and Jonathan, Jantsch
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Mice ,Electroporation ,Gene Knockdown Techniques ,Macrophages ,Animals ,Bone Marrow Cells ,Dendritic Cells ,RNA, Small Interfering ,Transfection - Abstract
Dendritic cells (DC) and macrophages (MΦ) play a pivotal role in antimicrobial defense, in the regulation of immune responses, and in maintaining tissue homeostasis. The analysis of DC and MΦ function relies on primary cells albeit these cells are known to be difficult to transfect. This makes the use of small interfering RNA (siRNA) for targeted manipulation of gene expression by RNA interference difficult. In the following chapter, we provide a detailed protocol for the successful transfer of siRNA via electroporation into a defined population of mouse bone marrow-derived MΦ or DC that does not cause toxicity to the myeloid cells or nonspecific alterations of their biological functions. Factors that influence the transfection and knockdown rate will be highlighted.
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- 2014
35. Electroporation of siRNA into Mouse Bone Marrow-Derived Macrophages and Dendritic Cells
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Valentin Schatz, Alexander T. Prechtel, Christian Bogdan, Alexander Steinkasserer, Isabel Siegert, and Jonathan Jantsch
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Gene knockdown ,Small interfering RNA ,medicine.anatomical_structure ,Chemistry ,Electroporation ,Gene Knockdown Techniques ,Myeloid-derived Suppressor Cell ,medicine ,Transfection ,Bone marrow ,Tissue homeostasis ,Cell biology - Abstract
Dendritic cells (DC) and macrophages (MΦ) play a pivotal role in antimicrobial defense, in the regulation of immune responses, and in maintaining tissue homeostasis. The analysis of DC and MΦ function relies on primary cells albeit these cells are known to be difficult to transfect. This makes the use of small interfering RNA (siRNA) for targeted manipulation of gene expression by RNA interference difficult. In the following chapter, we provide a detailed protocol for the successful transfer of siRNA via electroporation into a defined population of mouse bone marrow-derived MΦ or DC that does not cause toxicity to the myeloid cells or nonspecific alterations of their biological functions. Factors that influence the transfection and knockdown rate will be highlighted.
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- 2014
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36. Salt-responsive gut commensal modulates TH17 axis and disease
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Shinichi Sunagawa, Ralf A. Linker, Jonathan Jantsch, Beatriz F. Côrte-Real, Patrick Neubert, Sean M. Kearney, Lars Klug, Maik Gollasch, Ralf Dechend, Athanasios Typas, Michael Boschmann, Roman G. Gerlach, Marijana Basic, Anja Mähler, Lisa A. Maier, Lajos Markó, Eric J. Alm, Valentin Schatz, Kristoffer Forslund, Mariana Matus, Friedrich H. Kleiner, Scott W. Olesen, Diana A. Grohme, Alexander Krannich, Hendrik Bartolomaeus, Chuan Wu, Dominik Müller, Jens Titze, András Balogh, Stefanie Haase, Olga Vvedenskaya, Natalia Rakova, Peer Bork, Dmitry Tsvetkov, Stefan Kempa, Markus Kleinewietfeld, Paul I. Costea, Christian Frätzer, and Nicola Wilck
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0301 basic medicine ,Male ,Encephalomyelitis, Autoimmune, Experimental ,Indoles ,Encephalomyelitis ,Autoimmunity ,Blood Pressure ,Pilot Projects ,Gut flora ,Sodium Chloride ,medicine.disease_cause ,Lymphocyte Activation ,Article ,03 medical and health sciences ,Feces ,Mice ,Lactobacillus ,medicine ,Animals ,Humans ,Lymphocyte Count ,Symbiosis ,Multidisciplinary ,Bacteria ,biology ,Indoleacetic Acids ,Gastrointestinal Microbiome ,Experimental autoimmune encephalomyelitis ,Tryptophan ,Sodium, Dietary ,biology.organism_classification ,medicine.disease ,3. Good health ,Intestines ,Disease Models, Animal ,030104 developmental biology ,Blood pressure ,Immunology ,Hypertension ,Experimental pathology ,Th17 Cells - Abstract
A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions. This study was funded by grants from the German Centre for Cardiovascular Research (DZHK; BER 1.1 VD), the Center for Microbiome Informatics and Therapeutics, and the MetaCardis consortium. D.N.M., J.J. and M.G. were supported by the German Research Foundation (DFG). R.A.L. holds an endowed professorship supported by Novartis Pharma. M.K. was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium and by an Odysseus-grant of the Research Foundation Flanders (FWO), Belgium. L. reuteri was provided by L. Romani.
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37. Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen
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Isabel Siegert, Johannes Schödel, Manfred Nairz, Valentin Schatz, Katja Dettmer, Christopher Dick, Joanna Kalucka, Kristin Franke, Martin Ehrenschwender, Gunnar Schley, Angelika Beneke, Jörg Sutter, Matthias Moll, Claus Hellerbrand, Ben Wielockx, Dörthe M. Katschinski, Roland Lang, Bruno Galy, Matthias W. Hentze, Peppi Koivunen, Peter J. Oefner, Christian Bogdan, Günter Weiss, Carsten Willam, and Jonathan Jantsch
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Inflammation ,Lipopolysaccharides ,Iron ,Spectrophotometry, Atomic ,Mice, Transgenic ,Hypoxia-Inducible Factor 1, alpha Subunit ,Prolyl Hydroxylases ,Mice, Inbred C57BL ,Oxygen ,Mice ,lcsh:Biology (General) ,Tandem Mass Spectrometry ,Ferritins ,Animals ,Ample Oxygen ,Ferritin-Mediated Iron ,Hypoxia-Inducible Factor-1a, LPS ,lcsh:QH301-705.5 ,Protein Processing, Post-Translational ,Chromatography, High Pressure Liquid ,Signal Transduction - Abstract
Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron). peerReviewed
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