scholarly journals NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

2017 ◽  
Vol 214 (5) ◽  
pp. 1351-1370 ◽  
Author(s):  
Leslie Freeman ◽  
Haitao Guo ◽  
Clément N. David ◽  
W. June Brickey ◽  
Sushmita Jha ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Microbial Pathogens ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Caspase 1 ◽  
Physiological Relevance ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Pronounced Reduction ◽  
The Brain

Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer’s disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance, Nlrc4−/− and Nlrp3−/− mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis.

scholarly journals Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Ziwei Xu ◽  
Zi-mo Chen ◽  
Xiaoyan Wu ◽  
Linjie Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Pannexin 1 ◽  
Nlrp3 Inflammasome Activation ◽  
K2p Channels ◽  
Pore Forming Proteins ◽  
Molecular Patterns

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.

scholarly journals OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation

2018 ◽  
Vol 115 (7) ◽  
pp. E1530-E1539 ◽  
Author(s):  
Carlo Marchetti ◽  
Benjamin Swartzwelter ◽  
Fabia Gamboni ◽  
Charles P. Neff ◽  
Katrin Richter ◽  
...  
Keyword(s):  
Human Blood ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Plasma Concentrations ◽  
Metabolic Cost ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Caspase 1 ◽  
Healthy Humans

Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1β levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1β release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1β release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1β precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1β content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

scholarly journals Dampening the DAMPs: How Plants Maintain the Homeostasis of Cell Wall Molecular Patterns and Avoid Hyper-Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Daniela Pontiggia ◽  
Manuel Benedetti ◽  
Sara Costantini ◽  
Giulia De Lorenzo ◽  
Felice Cervone
Keyword(s):  
Plant Immunity ◽  
Microbial Pathogens ◽  
General Strategy ◽  
Plant Cell Walls ◽  
Cellular Mechanisms ◽  
The Family ◽  
Cellulose Breakdown ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Hydrolysis Of

Several oligosaccharide fragments derived from plant cell walls activate plant immunity and behave as typical damage-associated molecular patterns (DAMPs). Some of them also behave as negative regulators of growth and development, and due to their antithetic effect on immunity and growth, their concentrations, activity, time of formation, and localization is critical for the so-called “growth-defense trade-off.” Moreover, like in animals, over accumulation of DAMPs in plants provokes deleterious physiological effects and may cause hyper-immunity if the cellular mechanisms controlling their homeostasis fail. Recently, a mechanism has been discovered that controls the activity of two well-known plant DAMPs, oligogalacturonides (OGs), released upon hydrolysis of homogalacturonan (HG), and cellodextrins (CDs), products of cellulose breakdown. The potential homeostatic mechanism involves specific oxidases belonging to the family of berberine bridge enzyme-like (BBE-like) proteins. Oxidation of OGs and CDs not only inactivates their DAMP activity, but also makes them a significantly less desirable food source for microbial pathogens. The evidence that oxidation and inactivation of OGs and CDs may be a general strategy of plants for controlling the homeostasis of DAMPs is discussed. The possibility exists of discovering additional oxidative and/or inactivating enzymes targeting other DAMP molecules both in the plant and in animal kingdoms.

scholarly journals Emerging Role of the Inflammasome and Pyroptosis in Hypertension

2021 ◽  
Vol 22 (3) ◽  
pp. 1064
Author(s):  
Carmen De Miguel ◽  
Pablo Pelegrín ◽  
Alberto Baroja-Mazo ◽  
Santiago Cuevas
Keyword(s):  
Blood Pressure ◽  
Animal Models ◽  
Nlrp3 Inflammasome ◽  
Organ Damage ◽  
Subsequent Formation ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.

scholarly journals FROM THE BLOOD- BRAIN BARRIER TO BEHAVIOR

2017 ◽  
Vol 15 (1) ◽  
pp. 63-67
Author(s):  
Giulia Bivona ◽  
Bruna Lo Sasso ◽  
Luisa Agnello ◽  
Marcello Ciaccio
Keyword(s):  
Cell Death ◽  
Psychiatric Symptoms ◽  
Bronchial Tree ◽  
Microbial Pathogens ◽  
Danger Theory ◽  
Cognitive Disturbances ◽  
Molecular Patterns ◽  
Specific Symptoms ◽  
Endogenous Substances ◽  
The Brain

Research in the field of neuropsychoimmunology has enabled the researchers to show that cytokines target the brain to organize a "sickness response," which is fever, activation of hypothalamuspituitary- adrenal axis and behavioural alterations that develop in sick individuals. perypheral cytokines do not act directly on the brain; they trigger the production of cytokines in the brain parenchima itself, with a possible relay at the interface between internal milieeu and the brain, which are endothelial cells and circumven- tricular organs. The affective and behavioural changes that develop during in- fluenza are the product of a transient brain inflammatory response induced by the same proinflammatory cytokines that are produced in the bronchial tree. the cytokine pattern is distal to this phenomenon while the receptor molecules that decipher the molecular nature of microbial pathogens (pathogens associated molecular patterns PAMPs) at the membrane level of cells is a proximal factor. PAMPs are recognized by specialized receptors on innate immune cells that belong to the TOLL/IL-1 like recep-tor family. these receptors are phylogenetically old. the brain uses these receptors to defend itself against something different (several forms of brain injury that have nothing to do with infec- tious pathogens) from infectious pathogens. Assuming that the factors that activate these receptors involve endogenous substances derived by cell death (cell death by-products) is the concept at the origin of the danger theory. Evidence in favor of a citokines role in mediating mood disorders and cognitive disturbances in patients receiving cytokine immunotherapy is fast growing. (capuron e dantzer 2003) Several items of data support the role for cytokines in mediating a variety of non - specific symptoms that develop in patients suffering from disea- ses with an inflammatory component (cad, immunorheumatolic, neuropathologies (Cleeland 2003, Eikelenboom 2002, Gidron 2002, Kiecolt-Glaser and glaser 2002). These non-specific neurovegetative and psychiatric symptoms represent just another facet of the ingflammatory process and they are not necessarily derived from a direct cause-effect chain.

scholarly journals Necroptosis: The Release of Damage-Associated Molecular Patterns and Its Physiological Relevance

Immunity ◽  
2013 ◽  
Vol 38 (2) ◽  
pp. 209-223 ◽  
Author(s):  
Agnieszka Kaczmarek ◽  
Peter Vandenabeele ◽  
Dmitri V. Krysko
Keyword(s):  
Physiological Relevance ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

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 Nuclear Alarmin Cytokines in Inflammation

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Lili Jiang ◽  
Yijia Shao ◽  
Yao Tian ◽  
Changsheng Ouyang ◽  
Xiaohua Wang
Keyword(s):  
Inflammatory Response ◽  
Physiological Stress ◽  
Physiological State ◽  
High Mobility ◽  
Molecular Structures ◽  
Sterile Inflammation ◽  
Microbial Pathogens ◽  
Endogenous Proteins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathogen-associated molecular patterns (PAMPs) are some nonspecific and highly conserved molecular structures of exogenous specific microbial pathogens, whose products can be recognized by pattern recognition receptor (PRR) on innate immune cells and induce an inflammatory response. Under physiological stress, activated or damaged cells might release some endogenous proteins that can also bind to PRR and cause a harmful aseptic inflammatory response. These endogenous proteins were named damage-associated molecular patterns (DAMPs) or alarmins. Indeed, alarmins can also play a beneficial role in the tissue repair in certain environments. Besides, some alarmin cytokines have been reported to have both nuclear and extracellular effects. This group of proteins includes high-mobility group box-1 protein (HMGB1), interleukin (IL)-33, IL-1α, IL-1F7b, and IL-16. In this article, we review the involvement of nuclear alarmins such as HMGB1, IL-33, and IL-1α under physiological state or stress state and suggest a novel activity of these molecules as central initiators in the development of sterile inflammation.

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.

Cellular Labile Iron Activates NLRP3 Inflammasome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2723-2723 ◽  
Author(s):  
Kyohei Nakamura ◽  
Tohru Fujiwara ◽  
Tomonori Ishii ◽  
Hideo Harigae ◽  
Kouetsu Ogasawara
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Lysosomal Membrane Permeabilization ◽  
Labile Iron Pool ◽  
Caspase 1 ◽  
Cellular Iron ◽  
Nlrp3 Inflammasome Activation ◽  
Labile Iron ◽  
Iron Pool

Abstract Introduction. Monocytes/macrophages play an essential role in systemic iron homeostasis by their recycling and storage capacity of iron. Under chronic inflammatory condition, pro-inflammatory cytokines such as TNF-α and IL-1 stimulate production of hepcidin by liver cells, which in turn down-regulates iron exporter ferroportin expression on monocytes/macrophages. Thus, hepcidin/ferroportin axis contributes to the pathogenesis of anemia in chronic inflammation by restricting cellular iron export into plasma. Pro-inflammatory cytokine IL-1β is mainly produced by monocytes/macrophages througha molecular platform, called inflammasome. One of the best characterized members is NLRP3 inflammasome, which plays a central role in sterile inflammation in response to wide range of danger stimuli, including uric crystal, cholesterol crystal, silica and asbestos. Given that excess cellular iron increases the level of redox-active labile iron pool which is responsible for iron-mediated cytotoxicity, cellular labile iron might be sensed as a danger signal in monocytes/macrophages. In this study we addressed whether cellular labile iron activates NLRP3 inflammasome. Methods. Peripheral blood mononuclear cells (PBMCs) were isolated by density-gradient centrifugation from healthy donors. After 4 h priming with 10 ng/ml LPS, PBMCs were stimulated with various dose of ferric ammonium citrate (FAC) for 4 h. IL-1β production in culture supernatants was determined by ELISA. Cleaved caspase-1 and mature IL-1β was analyzed by western blot. Calcein-AM assay was used to determine cellular labile iron pool.To investigate the mechanism of NLRP3 inflammasome activation, total reactive oxygen species (ROS) detection assay and JC-10 mitochondrial membrane potential assay were performed. To evaluate lysosomal membrane permeabilization, PMA-differentiated THP-1 cells stained with Lyso Tracker were analyzed by fluorescence microscope. Results. FAC induced the concentration-dependent increase of the labile iron pool and secretion of IL-1β in LPS-primed human monocytes. Ferrous iron chelator, bipyridine significantly inhibited the IL-1β production, highlighting importance of cellular chelatable iron pool for IL-1β production. IL-1β production induced by FAC was abrogated by pan-caspase inhibitor as well as by caspase-1 specific inhibitor, suggesting that inflammasome-mediated caspase-1 activation is required for this process. Consistently, cleaved caspase-1 and mature IL-1β was confirmed by western blot analysis. We next addressed whether NLRP3 inflammasome is activated in response to cellular labile iron. NLRP3 inhibitor, glyburide significantly inhibited IL-1β production. Furthermore, FAC treatment induced IL-1β production in THP-1 cells, but not in NLRP3-deficient THP-1 cells, indicating that cellular iron activates NLRP3 inflammasome. Next, we addressed how cellular iron activates NLRP3 inflammasome. Potassium efflux is thought to be a common trigger of NLRP3 inflammasome activation. Consistently, IL-1β production was completely abrogated in high-potassium media, indicating that potassium efflux is required for iron-mediated NLRP3 inflammasome activation. Since cellular labile iron is involved in ROS generation through Fenton reactions, we next investigated the role of ROS in iron-mediated NLRP3 inflammasome activation. FAC treatment increased ROS levels of monocytes in concentration-dependent manner. Accordingly, the percentage of monocytes with decreased mitochondorial membrane potential was increased. N-acetyl cysteine inhibited FAC-induced IL-1β production, suggesting that ROS-mediated mitochondorial damage is involved in iron-mediated NLRP3 inflammasome activation. In addition, ROS-induced lysosomal membrane permeabilization was observed in FAC-treated THP-1 cells. A cathepsin B inhibitor, CA-074 methyl ester, inhibited IL-1β production, suggesting that ROS-mediated lysosomal damage is also involved in iron-mediated NLRP3 inflammasome activation. Conclusion. In this study, we found that cellular labile iron activates NLRP3 inflammasome through its redox activity. Because IL-1β has been reported to induce hepcidin synthesis, excess cellular iron in monocytes/macrophages might be implicated in a positive feedback loop for inflammation through NLRP3 inflammasome and hepcidin/ferroportin axis. Disclosures No relevant conflicts of interest to declare.

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