Induction, execution and clinical relevance of TNf- and TRAIL-induced necroptosis

Regulated necrosis is important in many (patho)physiological settings. In contrast to apoptosis, the molecular mechanisms of the induction and execution of regulated necrosis are only marginally understood. This thesis therefore presents detailed analyses of different aspects of regulated necrosis: the characterization of distinct routes to regulated necrosis, the identification of novel proteins involved in the execution of necroptosis and the study of the applicability of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL)-induced regulated necrosis in clinically relevant systems.Die regulierte Nekrose stellt einen wichtigen Mechanismus in physiologischen und pathophysiologischen Szenarien dar. Im Gegensatz zur Apoptose sind die Induktions- und Wirkungsmechanismen der regulierten Nekrose nur ansatzweise erforscht. Die vorliegende Arbeit präsentiert daher detaillierte Analysen über relevante Aspekte der regulierten Nekrose: die Charakterisierung verschiedener Wege zur regulierten Nekrose, die Beschreibung neuer Proteine, die an der Ausführung der TNF-induzierten Nekroptose beteiligt sind und die Untersuchung ob TRAIL-induzierte Nekroptose auch in klinisch relevanten Systemen angewendet werden kann

The TLR-NF-kB axis contributes to the monocytic inflammatory response against a virulent strain of Lichtheimia corymbifera , a causative agent of invasive mucormycosis

Invasive mucormycosis (IM) is a life-threatening infection caused by the fungal order Mucorales, its diagnosis is often delayed, and mortality rates range from 40-80% due to its rapid progression. Individuals suffering from hematological malignancies, diabetes mellitus, organ transplantations, and most recently COVID-19 are particularly susceptible to infection by Mucorales. Given the increase in the occurrence of these diseases, mucormycosis has emerged as one of the most common fungal infections in the last years. However, little is known about the host immune response to Mucorales. Therefore, we characterized the interaction among L. corymbifera— one of the most common causative agents of IM—and human monocytes, which are specialized phagocytes that play an instrumental role in the modulation of the inflammatory response against several pathogenic fungi. This study covered four relevant aspects of the host-pathogen interaction: i) The recognition of L. corymbifera by human monocytes. ii) The intracellular fate of L. corymbifera. iii) The inflammatory response by human monocytes against the most common causative agents of mucormycosis. iv) The main activated Pattern-Recognition Receptors (PRRs) inflammatory signaling cascades in response to L. corymbifera . Here, we demonstrate that L. corymbifera exhibits resistance to intracellular killing over 24 hours, does not germinate, and inflicts minimal damage to the host cell. Nonetheless, viable fungal spores of L. corymbifera induced early production of the pro-inflammatory cytokine IL-1β, and late release of TNF-α and IL-6 by human monocytes. Moreover, we revealed that IL-1β production predominantly depends on Toll-like receptors (TLRs) priming, especially via TLR4, while TNF-α is secreted via C-type lectin receptors (CTLs), and IL-6 is produced by synergistic activation of TLRs and CTLs. All these signaling pathways lead to the activation of NF-kB, a transcription factor that not only regulates the inflammatory response but also the apoptotic fate of monocytes during infection with L. corymbifera. Collectively, our findings provide new insights into the host-pathogen interactions, which may serve for future therapies to enhance the host inflammatory response to L. corymbifera

Phosphoinositide 3-OH Kinase Regulates Integrin-Dependent Processes in Neutrophils by Signaling through Its Effector ARAP3

ARAP3, a GTPase activating protein for Rho and Arf family GTPases, is one of many phosphoinositide 3-OH kinase (PI3K) effectors. In this study, we investigate the regulatory input of PI3K upstream of ARAP3 by analyzing neutrophils from an ARAP3 pleckstrin homology (PH) domain point mutation knock-in mouse (R302, 303A), in which ARAP3 is uncoupled from activation by PI3K. ARAP3 PH domain point mutant neutrophils are characterized by disturbed responses linked to stimulation by either integrin ligands or immobilized immune complexes. These cells exhibit increased β2 integrin inside-out signaling (binding affinity and avidity), and our work suggests the disturbed responses to immobilized immune complexes are secondary to this. In vitro, neutrophil chemotaxis is affected in the mutant. In vivo, ARAP3 PH domain point mutant bone marrow chimeras exhibit reduced neutrophil recruitment to the peritoneum on induction of sterile peritonitis and also reduced inflammation in a model for rheumatoid arthritis. The current work suggests a dramatic regulatory input of PI3K into the regulation of β2 integrin activity, and processes dependent on this, by signaling through its effector ARAP3. Copyright © 2012 by The American Association of Immunologists, Inc

The GAW/NDACC/SPARC Upper Troposphere and Lower Stratosphere (UTLS) Observation Workshop

The GAW (Global Atmosphere Watch) / NDACC (Network for the Detection of Atmospheric Composition Change) / SPARC Upper Troposphere and Lower Stratosphere (UTLS) Observation Workshop, hosted by the World Meteorological Organization (WMO) in Geneva, Switzerland, took place from 24-27 May 2016 and was attended by about 40 participants. The workshop aimed to bring together a diverse group of instrumentalists (from the groundbased, satellite, balloon, and aircraft communities), data analysts, and UTLS experts to synthesize current knowledge of chemical composition measurements in the UTLS

Politik und Wirtschaftsstrafrecht Abschlussbericht

UuStB Koeln(38)-870106361 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman