scholarly journals Natural Compounds as Regulators of NLRP3 Inflammasome-Mediated IL-1βProduction

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
József Tőzsér ◽  
Szilvia Benkő
Keyword(s):  
Immune Responses ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Mechanistic Explanation ◽  
Natural Compounds ◽  
The Other ◽  
Oxygen Species ◽  
Molecular Tools ◽  
Chronic Inflammatory Diseases ◽  
Physiological Processes

IL-1βis one of the main proinflammatory cytokines that regulates a broad range of immune responses and also participates in several physiological processes. The canonical production of IL-1βrequires multiprotein complexes called inflammasomes. One of the most intensively studied inflammasome complexes is the NLRP3 inflammasome. Its activation requires two signals: one signal “primes” the cells and induces the expression of NLRP3 and pro-IL-1β, while the other signal leads to the assembly and activation of the complex. Several stimuli were reported to function as the second signal including reactive oxygen species, lysosomal rupture, or cytosolic ion perturbation. Despite very intensive studies, the precise function and regulation of the NLRP3 inflammasome are still not clear. However, many chronic inflammatory diseases are related to the overproduction of IL-1βthat is mediatedviathe NLRP3 inflammasome. In this review, we aimed to provide an overview of studies that demonstrated the effect of plant-derived natural compounds on NLRP3 inflammasome-mediated IL-1βproduction. Although many of these studies lack the mechanistic explanation of their action, these compounds may be considered as complementary supplements in the treatment of chronic inflammatory diseases, consumed as preventive agents, and may also be considered as molecular tools to study NLRP3 function.

scholarly journals Cross talk between neutrophils and the microbiota

Blood ◽  
2019 ◽  
Vol 133 (20) ◽  
pp. 2168-2177 ◽  
Author(s):  
Dachuan Zhang ◽  
Paul S. Frenette
Keyword(s):  
Immune Responses ◽  
Cross Talk ◽  
Inflammatory Diseases ◽  
Host Immunity ◽  
Host Immune System ◽  
Chronic Inflammatory Diseases ◽  
Important Regulator ◽  
Cellular Mediators ◽  
Functional Modulation ◽  
And Function

Abstract The microbiota has emerged as an important regulator of the host immunity by the induction, functional modulation, or suppression of local and systemic immune responses. In return, the host immune system restricts translocation and fine tunes the composition and distribution of the microbiota to maintain a beneficial symbiosis. This paradigm applies to neutrophils, a critical component of the innate immunity, allowing their production and function to be influenced by microbial components and metabolites derived from the microbiota, and engaging them in the process of microbiota containment and regulation. The cross talk between neutrophils and the microbiota adjusts the magnitude of neutrophil-mediated inflammation on challenge while preventing neutrophil responses against commensals under steady state. Here, we review the major molecular and cellular mediators of the interactions between neutrophils and the microbiota and discuss their interplay and contribution in chronic inflammatory diseases and cancer.

scholarly journals The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

2021 ◽  
Vol 12 ◽  
Author(s):  
Panpan Chang ◽  
Hao Li ◽  
Hui Hu ◽  
Yongqing Li ◽  
Tianbing Wang
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Histone Deacetylase 6 ◽  
Physiological Processes ◽  
Class Iib ◽  
Underlying Mechanisms ◽  
Nlrp3 Inflammasomes ◽  
Insight Into

Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.

scholarly journals Exaggerated in vivo IL-17 responses discriminate recall responses in active TB

2019 ◽  
Author(s):  
Gabriele Pollara ◽  
Carolin T Turner ◽  
Gillian S Tomlinson ◽  
Lucy CK Bell ◽  
Ayesha Khan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Th17 Cells ◽  
Latent Infection ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Diseases ◽  
Host Immune Responses ◽  
Matrix Metalloproteinase 1 ◽  
First Time

AbstractHost immune responses at the site of Mycobacterium tuberculosis (Mtb) infection serve to contain the pathogen, but also mediate the pathogenesis of tuberculosis (TB) and onward transmission of infection. Interferon gamma (IFNγ) responses do not discriminate between protection and pathogenicity, but IL-17A/F responses, known to drive pathology in diverse chronic inflammatory diseases, have also been associated with TB pathogenesis in animal models. At the site of in vivo immune recall responses to Mtb modelled by the tuberculin skin test, we show for the first time that active TB in humans is also associated with exaggerated IL-17A/F expression, accumulation of Th17 cells and IL-17A/F bioactivity, including increased neutrophil recruitment and matrix metalloproteinase-1 expression directly implicated in TB pathogenesis. These features discriminate recall responses in patients with active TB from those with cured or latent infection and are also evident at the site of TB disease. Our data support targeting of this pathway in host-directed therapy for TB.

scholarly journals Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress

2021 ◽  
Vol 22 (5) ◽  
pp. 2549 ◽  
Author(s):  
Shin-ichi Hirano ◽  
Yusuke Ichikawa ◽  
Bunpei Sato ◽  
Haru Yamamoto ◽  
Yoshiyasu Takefuji ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Chronic Inflammatory Diseases ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation ◽  
Intracellular Organelles ◽  
Mitochondrial Oxidation ◽  
Nlrp3 Inflammasomes

Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).

scholarly journals Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Ahmad Alatshan ◽  
Szilvia Benkő
Keyword(s):  
Immune Responses ◽  
Nuclear Receptors ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Inflammatory Conditions ◽  
Physiological Processes ◽  
Nlrp3 Inflammasome Activation ◽  
Wide Range ◽  
Multiple Levels ◽  
Approved Drugs

Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.

scholarly journals Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases

2021 ◽  
Vol 44 (1) ◽  
pp. 16-35 ◽  
Author(s):  
Jin Kyung Seok ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
Hye Suk Lee ◽  
Joo Young Lee
Keyword(s):  
Pattern Recognition ◽  
Small Molecule ◽  
Nlrp3 Inflammasome ◽  
Small Molecule Inhibitors ◽  
Inflammatory Diseases ◽  
Cellular Damage ◽  
Receptor Protein ◽  
Current Status ◽  
Chronic Inflammatory Diseases ◽  
Molecular Patterns

AbstractInflammasomes are cytosolic pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) derived from invading pathogens and damaged tissues, respectively. Upon activation, the inflammasome forms a complex containing a receptor protein, an adaptor, and an effector to induce the autocleavage and activation of procaspase-1 ultimately culminating in the maturation and secretion of IL-1β and IL-18 and pyroptosis. Inflammasome activation plays an important role in host immune responses to pathogen infections and tissue repair in response to cellular damage. The NLRP3 inflammasome is a well-characterized pattern recognition receptor and is well known for its critical role in the regulation of immunity and the development and progression of various inflammatory diseases. In this review, we summarize recent efforts to develop therapeutic applications targeting the NLRP3 inflammasome to cure and prevent chronic inflammatory diseases. This review extensively discusses NLRP3 inflammasome-related diseases and current development of small molecule inhibitors providing beneficial information on the design of therapeutic strategies for NLRP3 inflammasome-related diseases. Additionally, small molecule inhibitors are classified depending on direct or indirect targeting mechanism to describe the current status of the development of pharmacological inhibitors.

scholarly journals The IRE1α stress signaling axis is a key regulator of neutrophil antimicrobial effector function

2019 ◽  
Author(s):  
B. H. Abuaita ◽  
G. J. Sule ◽  
T. L. Schultz ◽  
F. Gao ◽  
J. S. Knight ◽  
...  
Keyword(s):  
Immune Responses ◽  
Calcium Influx ◽  
Inflammatory Diseases ◽  
Effector Function ◽  
Stress Signaling ◽  
Oxygen Species ◽  
Signaling Axis ◽  
Mrsa Infection ◽  
Caspase 2

AbstractActivation of the endoplasmic reticulum stress sensor, IRE1α, is required for effective immune responses against bacterial infection and is associated with human inflammatory diseases where neutrophils are a key immune component. However, the specific role of IRE1α in regulating neutrophil effector function has not been studied. Here we show that infection-induced IRE1α activation licenses neutrophil antimicrobial capacity, including IL-1β production, NET formation, and MRSA killing. Inhibition of IRE1α diminished production of mitochondrial reactive oxygen species (mROS) and decreased CASPASE-2 activation, which both contributed to neutrophil antimicrobial activity. Mice deficient in Caspase-2 were highly susceptible to MRSA infection and failed to form NETs in a subcutaneous abscess. IRE1α activation enhanced calcium influx and citrullination of histone H3 (Cit-H3) independently of mROS production, suggesting that IRE1α coordinates multiple pathways required for NET formation. Our data demonstrate that the IRE1α-Caspase-2 axis is a major driver of neutrophil activity against MRSA infection and highlight the importance of IRE1α in neutrophil antibacterial function.One Sentence SummaryIRE1α controls neutrophil antimicrobial defenses

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