scholarly journals Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

2014 ◽  
Vol 34 (12) ◽  
pp. 1857-1867 ◽  
Author(s):  
George Trendelenburg
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Stroke Incidence ◽  
Multifactorial Diseases ◽  
Relevant Role ◽  
Metabolic Conditions

Analogous to Toll-like receptors, NOD-like receptors represent a class of pattern recognition receptors, which are cytosolic and constitute part of different inflammasomes. These large protein complexes are activated not only by different pathogens, but also by sterile inflammation or by specific metabolic conditions. Mutations can cause hereditary autoinflammatory systemic diseases, and inflammasome activation has been linked to many multifactorial diseases, such as diabetes or cardiovascular diseases. Increasing data also support an important role in different central nervous diseases such as stroke. Thus, the current knowledge of the functional role of this intracellular ‘master switch’ of inflammation is discussed with a focus on its role in ischemic stroke, neurodegeneration, and also with regard to the recent data which argues for a relevant role in other organs or biologic systems which influence stroke incidence or prognosis.

scholarly journals Inflammasome Activation in Pulmonary Arterial Hypertension

2022 ◽  
Vol 8 ◽  
Author(s):  
Anna Foley ◽  
Benjamin E. Steinberg ◽  
Neil M. Goldenberg
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Downstream Effectors ◽  
Inflammatory Stimuli ◽  
Affected Tissue ◽  
Pulmonary Arterial

Inflammasomes are multi-protein complexes that sense both infectious and sterile inflammatory stimuli, launching a cascade of responses to propagate danger signaling throughout an affected tissue. Recent studies have implicated inflammasome activation in a variety of pulmonary diseases, including pulmonary arterial hypertension (PAH). Indeed, the end-products of inflammasome activation, including interleukin (IL)-1β, IL-18, and lytic cell death (“pyroptosis”) are all key biomarkers of PAH, and are potentially therapeutic targets for human disease. This review summarizes current knowledge of inflammasome activation in immune and vascular cells of the lung, with a focus on the role of these pathways in the pathogenesis of PAH. Special emphasis is placed on areas of potential drug development focused on inhibition of inflammasomes and their downstream effectors.

scholarly journals Inflammasomes inMycobacterium tuberculosis-Driven Immunity

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Sebastian Wawrocki ◽  
Magdalena Druszczynska
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inflammatory Response ◽  
Immune Responses ◽  
Proinflammatory Cytokines ◽  
Immune Cells ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Host Immune Responses ◽  
Multimeric Protein

The development of effective innate and subsequent adaptive host immune responses is highly dependent on the production of proinflammatory cytokines that increase the activity of immune cells. The key role in this process is played by inflammasomes, multimeric protein complexes serving as a platform for caspase-1, an enzyme responsible for proteolytic cleavage of IL-1βand IL-18 precursors. Inflammasome activation, which triggers the multifaceted activity of these two proinflammatory cytokines, is a prerequisite for developing an efficient inflammatory response against pathogenicMycobacterium tuberculosis(M.tb). This review focuses on the role of NLRP3 and AIM2 inflammasomes inM.tb-driven immunity.

scholarly journals Role of the PE/PPE Family in Host–Pathogen Interactions and Prospects for Anti-Tuberculosis Vaccine and Diagnostic Tool Design

2020 ◽  
Vol 10 ◽  
Author(s):  
Jianing Qian ◽  
Run Chen ◽  
Honghai Wang ◽  
Xuelian Zhang
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Cell Interaction ◽  
Key Factors ◽  
Host Pathogen Interactions ◽  
Future Directions ◽  
Host Pathogen ◽  
Protein Research ◽  
Slow Growing

The pe/ppe genes are found in pathogenic, slow-growing Mycobacterium tuberculosis and other M. tuberculosis complex (MTBC) species. These genes are considered key factors in host-pathogen interactions. Although the function of most PE/PPE family proteins remains unclear, accumulating evidence suggests that this family is involved in M. tuberculosis infection. Here, we review the role of PE/PPE proteins, which are believed to be linked to the ESX system function. Further, we highlight the reported functions of PE/PPE proteins, including their roles in host cell interaction, immune response regulation, and cell fate determination during complex host-pathogen processes. Finally, we propose future directions for PE/PPE protein research and consider how the current knowledge might be applied to design more specific diagnostics and effective vaccines for global tuberculosis control.

scholarly journals Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

2020 ◽  
Vol 21 (14) ◽  
pp. 5097
Author(s):  
Aleksandar Arsenijevic ◽  
Bojana Stojanovic ◽  
Jelena Milovanovic ◽  
Dragana Arsenijevic ◽  
Nebojsa Arsenijevic ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Animal Studies ◽  
Current Knowledge ◽  
Specific Binding ◽  
Primary Biliary Cholangitis ◽  
Inflammasome Activation ◽  
Multimeric Complex ◽  
Galectin 3 ◽  
Binding Lectin

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

scholarly journals MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 413
Author(s):  
Inês L. S. Delgado ◽  
Bruno Carmona ◽  
Sofia Nolasco ◽  
Dulce Santos ◽  
Alexandre Leitão ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Polarity ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Cell Architecture ◽  
Septation Initiation Network ◽  
Control Organ ◽  
Multicellular Organisms

The MOB family proteins are constituted by highly conserved eukaryote kinase signal adaptors that are often essential both for cell and organism survival. Historically, MOB family proteins have been described as kinase activators participating in Hippo and Mitotic Exit Network/ Septation Initiation Network (MEN/SIN) signaling pathways that have central roles in regulating cytokinesis, cell polarity, cell proliferation and cell fate to control organ growth and regeneration. In metazoans, MOB proteins act as central signal adaptors of the core kinase module MST1/2, LATS1/2, and NDR1/2 kinases that phosphorylate the YAP/TAZ transcriptional co-activators, effectors of the Hippo signaling pathway. More recently, MOBs have been shown to also have non-kinase partners and to be involved in cilia biology, indicating that its activity and regulation is more diverse than expected. In this review, we explore the possible ancestral role of MEN/SIN pathways on the built-in nature of a more complex and functionally expanded Hippo pathway, by focusing on the most conserved components of these pathways, the MOB proteins. We discuss the current knowledge of MOBs-regulated signaling, with emphasis on its evolutionary history and role in morphogenesis, cytokinesis, and cell polarity from unicellular to multicellular organisms.

scholarly journals The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders

2019 ◽  
Vol 20 (9) ◽  
pp. 2142
Author(s):  
Lukas Nollet ◽  
Matthias Van Gils ◽  
Shana Verschuere ◽  
Olivier Vanakker
Keyword(s):  
Vitamin K ◽  
Current Knowledge ◽  
Pseudoxanthoma Elasticum ◽  
Ectopic Calcification ◽  
Multifactorial Diseases ◽  
Multiple Organs ◽  
Keutel Syndrome ◽  
Ectopic Mineralization ◽  
Related Compounds

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.

scholarly journals The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

2020 ◽  
Vol 21 (15) ◽  
pp. 5481
Author(s):  
Marianne R. Spalinger ◽  
Marlene Schwarzfischer ◽  
Michael Scharl
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Protein Complexes ◽  
Protein Tyrosine Phosphatases ◽  
Inflammasome Activation ◽  
Tyrosine Phosphatases ◽  
Tyrosine Residues ◽  
Inflammasome Activity ◽  
Activation Status

Inflammasomes are multi-protein complexes that mediate the activation and secretion of the inflammatory cytokines IL-1β and IL-18. More than half a decade ago, it has been shown that the inflammasome adaptor molecule, ASC requires tyrosine phosphorylation to allow effective inflammasome assembly and sustained IL-1β/IL-18 release. This finding provided evidence that the tyrosine phosphorylation status of inflammasome components affects inflammasome assembly and that inflammasomes are subjected to regulation via kinases and phosphatases. In the subsequent years, it was reported that activation of the inflammasome receptor molecule, NLRP3, is modulated via tyrosine phosphorylation as well, and that NLRP3 de-phosphorylation at specific tyrosine residues was required for inflammasome assembly and sustained IL-1β/IL-18 release. These findings demonstrated the importance of tyrosine phosphorylation as a key modulator of inflammasome activity. Following these initial reports, additional work elucidated that the activity of several inflammasome components is dictated via their phosphorylation status. Particularly, the action of specific tyrosine kinases and phosphatases are of critical importance for the regulation of inflammasome assembly and activity. By summarizing the currently available literature on the interaction of tyrosine phosphatases with inflammasome components we here provide an overview how tyrosine phosphatases affect the activation status of inflammasomes.

scholarly journals Biological functions controlled by manganese redox changes in mononuclear Mn-dependent enzymes

2017 ◽  
Vol 61 (2) ◽  
pp. 259-270 ◽  
Author(s):  
Wen Zhu ◽  
Nigel G.J. Richards
Keyword(s):  
Catalytic Mechanism ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Redox Properties ◽  
Metal Ligands ◽  
Manganese Ion ◽  
Hydrogen Bonding Interactions ◽  
Catalytically Active ◽  
Protein Environment

Remarkably few enzymes are known to employ a mononuclear manganese ion that undergoes changes in redox state during catalysis. Many questions remain to be answered about the role of substrate binding and/or protein environment in modulating the redox properties of enzyme-bound Mn(II), the nature of the dioxygen species involved in the catalytic mechanism, and how these enzymes acquire Mn(II) given that many other metal ions in the cell form more stable protein complexes. Here, we summarize current knowledge concerning the structure and mechanism of five mononuclear manganese-dependent enzymes: superoxide dismutase, oxalate oxidase (OxOx), oxalate decarboxylase (OxDC), homoprotocatechuate 3,4-dioxygenase, and lipoxygenase (LOX). Spectroscopic measurements and/or computational studies suggest that Mn(III)/Mn(II) are the catalytically active oxidation states of the metal, and the importance of ‘second-shell’ hydrogen bonding interactions with metal ligands has been demonstrated for a number of examples. The ability of these enzymes to modulate the redox properties of the Mn(III)/Mn(II) couple, thereby allowing them to generate substrate-based radicals, appears essential for accessing diverse chemistries of fundamental importance to organisms in all branches of life.

scholarly journals Transposable Elements in the Genome of Human Parasite Schistosoma mansoni: A Review

2021 ◽  
Vol 6 (3) ◽  
pp. 126
Author(s):  
Gisele Strieder Philippsen
Keyword(s):  
Gene Duplication ◽  
Transposable Elements ◽  
Schistosoma Mansoni ◽  
Dna Sequences ◽  
Current Knowledge ◽  
Coding Sequences ◽  
Human Parasite ◽  
Relevant Role ◽  
Duplication Events

Transposable elements (TEs) are DNA sequences able to transpose within the host genome and, consequently, influence the dynamics of evolution in the species. Among the possible effects, TEs insertions may alter the expression and coding patterns of genes, leading to genomic innovations. Gene-duplication events, resulting from DNA segmental duplication induced by TEs transposition, constitute another important mechanism that contributes to the plasticity of genomes. This review aims to cover the current knowledge regarding TEs in the genome of the parasite Schistosoma mansoni, an agent of schistosomiasis—a neglected tropical disease affecting at least 250 million people worldwide. In this context, the literature concerning TEs description and TEs impact on the genomic architecture for S. mansoni was revisited, displaying evidence of TEs influence on schistosome speciation—mediated by bursts of transposition—and in gene-duplication events related to schistosome–host coevolution processes, as well several instances of TEs contribution into the coding sequences of genes. These findings indicate the relevant role of TEs in the evolution of the S. mansoni genome.

scholarly journals Inflammasome activation in neutrophils of patients with severe COVID-19

2022 ◽  
Author(s):  
Karen Aymonnier ◽  
Julie Ng ◽  
Laura E Fredenburgh ◽  
Katherin Zambrano-Vera ◽  
Patrick Münzer ◽  
...  
Keyword(s):  
Time Lapse ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Microtubule Organizing Center ◽  
Reporter Mice ◽  
Organizing Center ◽  
Monocytes And Macrophages ◽  
Histone Citrullination ◽  
Net Release

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was observed in neutrophils with an intact poly-lobulated nucleus, suggesting early formation during neutrophil activation. Additionally, 40% of nuclei were positive for citrullinated histone H3, and there was a significant correlation between speck formation and nuclear histone citrullination. Time-lapse microscopy in LPS-stimulated neutrophils from fluorescent ASC reporter mice showed that ASC speck formed transiently and at the microtubule organizing center, long before NET release. Our study shows that ASC speck is present in neutrophils from COVID-19 patients with respiratory failure and that it forms early in NETosis. Our findings suggest that inhibition of neutrophil inflammasomes may be beneficial in COVID-19.

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