scholarly journals Inflammasomes in Teleosts: Structures and Mechanisms That Induce Pyroptosis during Bacterial Infection

2021 ◽  
Vol 22 (9) ◽  
pp. 4389
Author(s):  
Natsuki Morimoto ◽  
Tomoya Kono ◽  
Masahiro Sakai ◽  
Jun-ichi Hikima
Keyword(s):  
Inflammatory Responses ◽  
Current Knowledge ◽  
Adaptor Protein ◽  
Protective Role ◽  
Inflammasome Activation ◽  
Multiple Protein ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Oligomerization Domain

Pattern recognition receptors (PRRs) play a crucial role in inducing inflammatory responses; they recognize pathogen-associated molecular patterns, damage-associated molecular patterns, and environmental factors. Nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptors (NLRs) are part of the PRR family; they form a large multiple-protein complex called the inflammasome in the cytosol. In mammals, the inflammasome consists of an NLR, used as a sensor molecule, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as an adaptor protein, and pro-caspase1 (Casp1). Inflammasome activation induces Casp1 activation, promoting the maturation of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, and the induction of inflammatory cell death called pyroptosis via gasdermin D cleavage in mammals. Inflammasome activation and pyroptosis in mammals play important roles in protecting the host from pathogen infection. Recently, numerous inflammasome-related genes in teleosts have been identified, and their conservation and/or differentiation between their expression in mammals and teleosts have also been elucidated. In this review, we summarize the current knowledge of the molecular structure and machinery of the inflammasomes and the ASC-spec to induce pyroptosis; moreover, we explore the protective role of the inflammasome against pathogenic infection in teleosts.

scholarly journals DAMPening Inflammation by Modulating TLR Signalling

2010 ◽  
Vol 2010 ◽  
pp. 1-21 ◽  
Author(s):  
A. M. Piccinini ◽  
K. S. Midwood
Keyword(s):  
Immune System ◽  
Tissue Damage ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Feedback Loops ◽  
Inflammatory Gene Expression ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Tlr Signalling

Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

scholarly journals The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

2021 ◽  
Vol 22 (3) ◽  
pp. 1271
Author(s):  
Laura Urwanisch ◽  
Michela Luciano ◽  
Jutta Horejs-Hoeck
Keyword(s):  
Nlrp3 Inflammasome ◽  
Innate Immune System ◽  
Inflammatory Cell ◽  
Current Knowledge ◽  
Innate Immune ◽  
Leukemic Cells ◽  
Different Types ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1β is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia.

scholarly journals Targeting Innate Immunity to Combat Cutaneous Stress: The Vitiligo Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Katia Boniface ◽  
Thierry Passeron ◽  
Julien Seneschal ◽  
Meri K. Tulic
Keyword(s):  
Immune Response ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Danger Signals ◽  
Multiple Factors ◽  
Autoimmune Condition ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Multiple factors are involved in the process leading to melanocyte loss in vitiligo including environmental triggers, genetic polymorphisms, metabolic alterations, and autoimmunity. This review aims to highlight current knowledge on how danger signals released by stressed epidermal cells in a predisposed patient can trigger the innate immune system and initiate a cascade of events leading to an autoreactive immune response, ultimately contributing to melanocyte disappearance in vitiligo. We will explore the genetic data available, the specific role of damage-associated-molecular patterns, and pattern-recognition receptors, as well as the cellular players involved in the innate immune response. Finally, the relevance of therapeutic strategies targeting this pathway to improve this inflammatory and autoimmune condition is also discussed.

scholarly journals Research Progress on the Role of Inflammasomes in Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Kun Chi ◽  
Xiaodong Geng ◽  
Chao Liu ◽  
GuangYan Cai ◽  
Quan Hong
Keyword(s):  
Kidney Disease ◽  
Inflammatory Responses ◽  
Kidney Diseases ◽  
Interleukin 1 ◽  
Research Progress ◽  
Chronic Kidney Diseases ◽  
Caspase 1 ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Inflammasomes are multimeric complexes composed of cytoplasmic sensors, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC or PYCARD), and procaspase-1 and play roles in regulating caspase-dependent inflammation and cell death. Inflammasomes are assembled by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate inflammatory responses by activating caspase-1. Activated caspase-1 promotes the release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and eventually induces pyroptosis. Inflammasomes are closely related to kidney diseases. In particular, the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome has been shown to cause acute and chronic kidney diseases by regulating canonical and noncanonical mechanisms of inflammation. Small-molecule inhibitors that target NLRP3 and other components of the inflammasome are potential options for the treatment of kidney-related diseases such as diabetic nephropathy. This article will focus on the research progress on inflammasomes and the key pathogenic roles of inflammasomes in the development and progression of kidney diseases and explore the potential of this intracellular inflammation to further prevent or block the development of the kidney disease.

scholarly journals Toll-Like Receptors and Myocardial Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-21 ◽  
Author(s):  
Yan Feng ◽  
Wei Chao
Keyword(s):  
Animal Studies ◽  
Myocardial Injury ◽  
Myocardial Inflammation ◽  
Septic Cardiomyopathy ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
Animal Data ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Toll-like receptors (TLRs) are a member of the innate immune system. TLRs detect invading pathogens through the pathogen-associated molecular patterns (PAMPs) recognition and play an essential role in the host defense. TLRs can also sense a large number of endogenous molecules with the damage-associated molecular patterns (DAMPs) that are produced under various injurious conditions. Animal studies of the last decade have demonstrated that TLR signaling contributes to the pathogenesis of the critical cardiac conditions, where myocardial inflammation plays a prominent role, such as ischemic myocardial injury, myocarditis, and septic cardiomyopathy. This paper reviews the animal data on (1) TLRs, TLR ligands, and the signal transduction system and (2) the important role of TLR signaling in these critical cardiac conditions.

scholarly journals cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis

2019 ◽  
Vol 5 (5) ◽  
pp. eaav5562 ◽  
Author(s):  
Ruochan Chen ◽  
Ling Zeng ◽  
Shan Zhu ◽  
Jiao Liu ◽  
Herbert J. Zeh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
Proof Of Concept ◽  
Potential Therapeutic Target ◽  
Camp Metabolism ◽  
Camp Hydrolysis ◽  
Insight Into

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11−/−), or Gsdmd inactivation (GsdmdI105N/I105N) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

scholarly journals Schistosome tegumental ecto-apyrase (SmATPDase1) degrades exogenous pro-inflammatory and pro-thrombotic nucleotides.

2014 ◽  
Author(s):  
Akram A Da'dara ◽  
Rita Bhardwaj ◽  
Yasser MB Ali ◽  
Patrick Skelly
Keyword(s):  
Thrombus Formation ◽  
Functional Characterization ◽  
Host Cells ◽  
Dependent Manner ◽  
Host Immune Responses ◽  
Genes Encoding ◽  
Molecular Patterns ◽  
Parasitic Worms ◽  
Damage Associated Molecular Patterns

Schistosomes are parasitic worms that can survive in the hostile environment of the human bloodstream where they appear refractory to both immune elimination and thrombus formation. We hypothesize that parasite migration in the bloodstream can stress the vascular endothelium causing this tissue to release chemicals alerting responsive host cells to the stress. Such chemicals are called damage associated molecular patterns (DAMPs) and among the most potent is the proinflammatory mediator, adenosine triphosphate (ATP). Furthermore, the ATP derivative ADP is a pro-thrombotic molecule that acts as a strong activator of platelets. Schistosomes are reported to possess at their host interactive tegumental surface a series of enzymes that could, like their homologs in mammals, degrade extracellular ATP and ADP. These are alkaline phosphatase (SmAP), phosphodiesterase (SmNPP-5) and ATP diphosphohydrolase (SmATPDase1). In this work we employ RNAi to knock down expression of the genes encoding these enzymes in the intravascular life stages of the parasite. We then compare the abilities of these parasites to degrade exogenously added ATP and ADP. . We find that only SmATPDase1-suppressed parasites are significantly impaired in their ability to degrade these nucleotides. Suppression of SmAP or SmNPP-5 does not appreciably affect the worms’ ability to catabolize ATP or ADP. These findings are confirmed by the functional characterization of the enzymatically active, full-length recombinant SmATPDase1 expressed in CHO-S cells. The enzyme is a true apyrase; SmATPDase1 degrades ATP and ADP in a cation dependent manner. Optimal activity is seen at alkaline pH. The Km of SmATPDase1 for ATP is 0.4 ±0.02 mM and for ADP, 0.252 ± 0.02 mM. The results confirm the role of tegumental SmATPDase1 in the degradation of the exogenous pro-inflammatory and pro-thrombotic nucleotides ATP and ADP by live intravascular stages of the parasite. By degrading host inflammatory signals like ATP, and pro-thrombotic signals like ADP, these parasite enzymes may minimize host immune responses, inhibit blood coagulation and promote schistosome survival.)

Lung epithelial NOX/DUOX and respiratory virus infections

2014 ◽  
Vol 128 (6) ◽  
pp. 337-347 ◽  
Author(s):  
Nathalie Grandvaux ◽  
Mélissa Mariani ◽  
Karin Fink
Keyword(s):  
Respiratory Virus ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Conditional Knockout ◽  
In Vivo Studies ◽  
Virus Infections ◽  
Lung Epithelial ◽  
Respiratory Virus Infections

Determining the role of NADPH oxidases in the context of virus infection is an emerging area of research and our knowledge is still sparse. The expression of various isoforms of NOX/DUOX (NADPH oxidase/dual oxidase) in the epithelial cells (ECs) lining the respiratory tract renders them primary sites from which to orchestrate the host defence against respiratory viruses. Accumulating evidence reveals distinct facets of the involvement of NOX/DUOX in host antiviral and pro-inflammatory responses and in the control of the epithelial barrier integrity, with individual isoforms mediating co-operative, but surprisingly also opposing, functions. Although in vivo studies in mice are in line with some of these observations, a complete understanding of the specific functions of epithelial NOX/DUOX awaits lung epithelial-specific conditional knockout mice. The goal of the present review is to summarize our current knowledge of the role of individual NOX/DUOX isoforms expressed in the lung epithelium in the context of respiratory virus infections so as to highlight potential opportunities for therapeutic intervention.

Abstract 288: High Mobility Group Box 1 (HMGB1) is Involved in the Physiopathology of Post-Cardiac Arrest Syndrome

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Emilie Boissady ◽  
Cynthia El Hedjaj ◽  
Matthias Kohlhauer ◽  
Bijan Ghaleh ◽  
Renaud Tissier
Keyword(s):  
Cardiac Arrest ◽  
High Mobility ◽  
Brain Regions ◽  
Clinical Parameter ◽  
High Mobility Group ◽  
Neurological Dysfunction ◽  
Blood Levels ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Introduction: After cardiac arrest, a sepsis-like syndrome is observed and contributes to poor prognosis. Hypothesis: This syndrome could be provoked by the massive release of Damage Associated Molecular Patterns (DAMP). Our aim was to investigate the role of the High mobility group box 1 (HMGB1), a well-characterized nuclear DAMP, in an experimental model of cardiac arrest. Methods: Rabbits were anesthetized and submitted to 10 min of ventricular fibrillation. After resuscitation, they either received an administration of the inhibitor of HMGB1 release glycyrrhizin (4 mg/kg i.v.. (GL group, n=6), or saline (5 ml, i.v.; CT group, n=6). Two additional groups received glycyrrhizin (n=4) or saline (n=4) alone without cardiac arrest (Sham groups). Blood samples were withdrawn to evaluate the kinetics of HMGB1 release. After awakening, survival and neurological dysfunction were evaluated during 3 days. Animals were then euthanized and brain histologic damages were assessed (fluorojade-C staining). Results: In the Sham groups, glycyrrhizin did not modify hemodynamic nor clinical parameter as compared to saline. In the CT group, HMGB1 blood levels increased since 30 min after cardiac arrest and remained elevated until the end of the follow-up. This increase in HMGB1 concentrations was significantly attenuated in GL vs CR (18±1 vs 29±5 and ng/ml at 30 min after cardiac arrest, respectively). Neurological dysfunction score or survival were not significantly improved in GL vs CT (e.g., survival = 50 vs 33 % at day 3 in GT vs CT group). However, fluorojade C staining showed a dramatic attenuation of degenerating neurons in GL vs CT groups in all brain regions (e.g., 7±3 vs 32±10 neurons/field in cortex, respectively). Conclusion: HMGB1 played a key role in early inflammation and promoted neuronal death after cardiac arrest. Its inhibition alone does not provide sufficient benefits to improve the clinical outcome. It emphasizes the importance of other contributors, beyond inflammation and neurons cell death. Adjunction of HMGB1 inhibitors to other therapies could still be of interest.

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