Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia ...handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an “on-demand” functional network in order to improve pathogenic α-syn clearance.
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•Microglia rapidly engulf exogenous α-synuclein but hesitate in its degradation•α-synuclein is transferred between microglia through tunneling nanotubes•Healthy microglia donate mitochondria to α-synuclein overloaded cells•Sharing the α-synuclein burden attenuated the inflammatory microglia profile
Microglia form F-actin dependent intercellular networks to transfer α-synuclein fibrils to neighboring microglial cells for degradation and clearance. Impairment in this process, as seen with Parkinson’s disease mutations, leads to increased inflammatory profiles and cell death.
Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in ...neurodegeneration and cognitive decline
. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release
. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice
, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.
The European Court of Justice is one of the most important actors in the process of European integration. Political science still struggles to understand its significance, with recent scholarship ...emphasizing how closely rulings reflect member states’ preferences. In this book, I argue that the implications of the supremacy and direct effect of the EU law have still been overlooked. As it constitutionalizes an intergovernmental treaty, the European Union has a detailed set of policies inscribed into its constitution that are extensively shaped by the Court’s case law. If rulings have constitutional status, their impact is considerable, even if the Court only occasionally diverts from member states’ preferences. By focusing on the four freedoms of goods, services, persons, and capital, as well as citizenship rights, the book analyses how the Court’s development of case law has ascribed a broad meaning to these freedoms. The constitutional status of this case law constrains policymaking at the European and member-state levels. Different case studies show how major pieces of EU legislation cannot move beyond case law but have to codify its principles. Judicialization is important in the EU. It also directly constrains member-state policies. Court rulings oriented towards individual disputes are difficult to translate into general policies, and into administrative practices. Policy options are thereby withdrawn from majoritarian decision-making. As the Court cannot be overruled, short of a Treaty change, its case law casts a long shadow over policymaking in the European Union and its member states, undermining the legitimacy of this political order.
Immunotherapy in sepsis - brake or accelerate? Steinhagen, Folkert; Schmidt, Susanne V.; Schewe, Jens-Christian ...
Pharmacology & therapeutics,
April 2020, 2020-04-00, 20200401, Letnik:
208
Journal Article
Recenzirano
Odprti dostop
Sepsis, a life threating syndrome characterized by organ failure after infection, is the most common cause of death in hospitalized patients. The treatment of sepsis is generally supportive in ...nature, involving the administration of intravenous fluids, vasoactive substances and oxygen plus antibiotics to eliminate the pathogen. No drugs have been approved specifically for the treatment of sepsis, and clinical trials of potential therapies have failed to reduce mortality - suggesting that new approaches are needed. Abnormalities in the immune response elicited by the pathogen, ranging from excessive inflammation to immunosuppression, contribute to disease pathogenesis. Although hundreds of immunomodulatory agents are potentially available, it remains unclear which patient benefits from which immune therapy at a given time point. Results indicate the importance of personalized therapy, specifically the need to identify the type of intervention required by each individual patient at a given point in the disease process. To address this issue will require using biomarkers to stratify patients based on their individual immune status. This article reviews recent and ongoing clinical investigations using immunostimulatory or immunosuppressive therapies against sepsis including non-pharmacological and novel preclinical approaches.
Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the ...transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.
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•Macrophages react with specific transcriptional programming upon distinct signals•Activation by TNF, PGE2, and P3C activates a STAT4-associated transcriptional program•NFKB1, JUNB, and CREB1 are central transcription factors of macrophage activation•Inflammatory signatures are lost in alveolar macrophages from COPD patients
The abundant literature on the UK's Brexit-decision has focused on explaining the politicization and preference formation leading up to the referendum. But the institutional background has received ...much less attention. I argue that as a common-law country with a tradition of parliamentary sovereignty, the UK exhibits institutional features that pose a significant mismatch to the prevailing policymaking mode in the European Union. The latter relies heavily on the constitutionalization of the EU-Treaties with the four freedoms, competition law, and citizenship rights, and accords an extraordinary role to the European Court of Justice in policymaking. Constitutionalized European rules regarding freedom of movement and EU citizens' access to the welfare state drove the politicization of EU-membership in the UK. To understand why 'taking back control' found such resonance, it is important to reflect the core features of the UK polity.
Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that ...occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings.
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•Macrophages adopt a transient metabolic state in response to TLR4 activation•MyD88 and TRIF synergistically facilitate signaling-driven changes in metabolism•Increases in glycolysis and ATP-citrate lyase activity foster histone acetylation•ATP-citrate lyase governs gene induction of a distinct LPS responsive gene set
TLR4 activation by LPS induces defined transcriptional cascades. Lauterbach et al. provide evidence that TLR activation induces a transient metabolic state that supports the transcriptional response. Mechanistically, they show that concerted increases in glycolytic flux and ATP-citrate lyase activity foster histone acetylation.
Extant research has shown that firms with high levels of entrepreneurial orientation (EO) outperform competitors. The present study sheds light on this performance relationship in large, publicly ...listed high-tech firms by examining whether the strength of this relationship depends upon the CEO’s narcissism, an executive personality trait recently debated controversially in both academic and practitioner publications. A theoretically derived research model is empirically validated by means of multisource secondary data for 41 S&P 500 firms from 2005 to 2007. Findings indicate that narcissistic CEOs usually weaken the EO-performance relationship, although the opposite is true under some conditions, such as in highly concentrated and dynamic markets.
Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been ...accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.
The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other ...mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy via the stress-responsive co-chaperone FK506-binding protein 51. We identify the matrix metalloproteinase 9 (MMP9) as one of the proteins secreted in response to stress. Using cellular assays and in vivo microdialysis, we further find that stress-enhanced MMP9 secretion increases the cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF). BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders.
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