scholarly journals ASC Speck Formation after Inflammasome Activation in Primary Human Keratinocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Nikola Smatlik ◽  
Stefan Karl Drexler ◽  
Marc Burian ◽  
Martin Röcken ◽  
Amir Sadegh Yazdi
Keyword(s):  
Cell Death ◽  
Protein Complexes ◽  
Human Keratinocytes ◽  
Inflammasome Activation ◽  
Primary Human Keratinocytes ◽  
Cytosolic Protein ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Inducible Protein ◽  
Human Primary Keratinocytes

Chronic UV irradiation results in many changes in the skin, including hyperplasia, changes in dermal structures, and alteration of pigmentation. Exposure to UVB leads to cutaneous damage, which results in inflammation characterized by increased NF-κB activation and the induction of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin- (IL-) 1, or IL-8. IL-1 secretion is the result of inflammasome activation which is besides apoptosis, a result of acute UVB treatment. Inflammasomes are cytosolic protein complexes whose formation results in the activation of proinflammatory caspase-1. Key substrates of caspase-1 are IL-1β and IL-18, and the cytosolic protein gasdermin D (GSDMD), which is involved in inflammatory cell death. Here, we demonstrate that UVB-induced inflammasome activation leads to the formation of ASC specks. Our findings show that UVB provokes ASC speck formation in human primary keratinocytes prior to cell death, and that specks are, opposed to the perinuclear cytosolic localization in myeloid cells, formed in the nucleus. Additionally, we showed by RNAi that NLRP1 and not NLRP3 is the major inflammasome responsible for UVB sensing in primary human keratinocytes. Formation of ASC specks indicates inflammasome assembly and activation as their formation in hPKs depends on the presence of NLRP1 and partially on NLRP3. Nuclear ASC specks are not specific for NLRP1/NLRP3 inflammasome activation, as the activation of the AIM2 inflammasome by cytosolic DNA results in ASC specks too. These nuclear ASC specks putatively link cell death to inflammasome activation, possibly by binding of IFI16 (gamma-interferon-inducible protein) to ASC. ASC can interact upon UVB sensing via IFI16 with p53, linking cell death to ASC speck formation.

scholarly journals New insights in caspase-11 functions in noncanonical inflammasome signalling

Inflammasome ◽  
2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Mélanie Bodnar ◽  
Virginie Petrilli
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Nucleotide Binding Domain ◽  
Gram Negative ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Dependent Pathway

AbstractInflammasomes are multi-protein complexes that play a crucial role in innate immunity. They are assembled by cytosolic sensors of the Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLR) and PYrin and HIN (PYHIN) domain-containing protein families upon sensing various pathogens and danger signals. Inflammasome formation culminates in caspase-1 activation, which causes the cleavage of pro-IL-1β and pro- IL-18 into active cytokines; this eventually results in the induction of an inflammatory cell death called pyroptosis. Recent data using Gram-negative bacteria suggests a role for caspase-11 not only in NLRP3 inflammasome activation but also in a caspase-1- and inflammasome-independent cell death. This novel caspase-11-dependent pathway is critical to control infection by Gram-negative bacteria and has been named the noncanonical inflammasome.

scholarly journals Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

2015 ◽  
Vol 308 (10) ◽  
pp. L1058-L1067 ◽  
Author(s):  
Sung-Soo Jung ◽  
Jong-Seok Moon ◽  
Jin-Fu Xu ◽  
Emeka Ifedigbo ◽  
Stefan W. Ryter ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Protein Complexes ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Inflammasomes are cytosolic protein complexes that promote the cleavage of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Among the known inflammasomes, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3)-dependent inflammasome is critically involved in the pathogenesis of various acute or chronic inflammatory diseases. Carbon monoxide (CO), a gaseous molecule physiologically produced in cells and tissues during heme catabolism, can act as an anti-inflammatory molecule and a potent negative regulator of Toll-like receptor signaling pathways. To date, the role of CO in inflammasome-mediated immune responses has not been fully investigated. Here, we demonstrated that CO inhibited caspase-1 activation and the secretion of IL-1β and IL-18 in response to lipopolysaccharide (LPS) and ATP treatment in bone marrow-derived macrophages. CO also inhibited IL-18 secretion in response to LPS and nigericin treatment, another NLRP3 inflammasome activation model. In contrast, CO did not suppress IL-18 secretion in response to LPS and poly(dA:dT), an absent in melanoma 2 (AIM2)-mediated inflammasome model. LPS and ATP stimulation induced the formation of complexes between NLRP3 and apoptosis-associated speck-like protein, or NLRP3 and caspase-1. CO treatment inhibited these molecular interactions that were induced by LPS and ATP. Furthermore, CO inhibited mitochondrial ROS generation and the decrease of mitochondrial membrane potential induced by LPS and ATP in macrophages. We also observed that the inhibitory effect of CO on the translocation of mitochondrial DNA into the cytosol was associated with suppression of cytokine secretion. Our results suggest that CO negatively regulates NLRP3 inflammasome activation by preventing mitochondrial dysfunction.

scholarly journals Trichomonas vaginalis Induces NLRP3 Inflammasome Activation and Pyroptotic Cell Death in Human Macrophages

2018 ◽  
Vol 11 (1) ◽  
pp. 86-98 ◽  
Author(s):  
Angelica Montenegro Riestra ◽  
J. Andrés Valderrama ◽  
Kathryn A. Patras ◽  
Sharon D. Booth ◽  
Xing Yen Quek ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nlrp3 Inflammasome ◽  
Trichomonas Vaginalis ◽  
Inflammasome Activation ◽  
Cell Detection ◽  
Human Macrophages ◽  
Sexually Transmitted ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Trichomonas vaginalis is a sexually transmitted, eukaryotic parasite that causes trichomoniasis, the most common nonviral, sexually transmitted disease in the USA and worldwide. Little is known about the molecular mechanisms involved in the host immune response to this widespread parasite. Here we report that T. vaginalis induces NLRP3 inflammasome activation in human macrophages, leading to caspase-1 activation and the processing of pro-IL-1β to the mature and bioactive form of the cytokine. Using inhibitor-based approaches, we show that NLRP3 activation by T. vaginalis involves host cell detection of extracellular ATP via P2X7 receptors and potassium efflux. In addition, our data reveal that T. vaginalis inflammasome activation induces macrophage inflammatory cell death by pyroptosis, known to occur via caspase-1 cleavage of the gasdermin D protein, which assembles to form pores in the host cell membrane. We found that T. vaginalis-induced cytolysis of macrophages is attenuated in gasdermin D knockout cells. Lastly, in a murine challenge model, we detected IL-1β production in vaginal fluids in response to T. vaginalis infection in vivo. Together, our findings mechanistically dissect how T. vaginalis contributes to the production of the proinflammatory IL-1β cytokine and uncover pyroptosis as a mechanism by which the parasite can trigger host macrophage cell death.

scholarly journals Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Bora Tastan ◽  
Burak I. Arioz ◽  
Kemal Ugur Tufekci ◽  
Emre Tarakcioglu ◽  
Ceren Perihan Gonul ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Forced Swim Test ◽  
Sickness Behavior ◽  
Dimethyl Fumarate ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both in vitro and in vivo. For in vitro studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF’s effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For in vivo studies, 12–14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both in vivo and in vitro. Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms.

scholarly journals Lycopus lucidus Turcz exerts neuroprotective effect against H2O2‑induced neuroinflammation by inhibiting NLRP3 inflammasome activation in cortical neurons

2021 ◽  
Author(s):  
Hyunseong Kim ◽  
Jin Young Hong ◽  
Wan-Jin Jeon ◽  
Junseon Lee ◽  
Seung Ho Baek ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Cortical Neurons ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Synaptic Connectivity ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Rat Cortical Neurons

Abstract Background Central nervous system (CNS) injuries are a leading cause of permanent functional impairment in humans. Nerve damage can be aggravated by neuroinflammation mediated by protein complexes known as inflammasomes, such as the NLRP3 inflammasome which is a key mediator of caspase-1 and interleukin-1β (IL-1β) /interleukin-18 (IL-18) activation. Lycopus lucidus Turcz (LLT) is a traditional medicinal herb that exerts therapeutic effects against oxidative stress, inflammation, and angiogenesis; however, it remains unclear whether LLT can directly protect neurons against damage, and the underlying molecular mechanisms are poorly understood. Methods We investigated the neuroprotective effect of LLT against hydrogen peroxide (H2O2)-induced neuronal damage in cultured primary rat cortical neurons, as well as the potential underlying mechanisms. Neuronal viability and cell death assays were used to determine the effects of LLT on neuroprotection, while the mode of cell death was confirmed using flow cytometry. Changes in the expression of inflammatory factors involved in activation of the NLRP3 inflammasome were measured using immunocytochemistry (ICC) and confirmed by real-time PCR. And, we analyzed that the effect of LLT on neurotrophic factors secretion and synaptic connectivity using ICC in H2O2-induced neuron at 7 days in vitro. Results LLT effectively protected cultured rat cortical neurons from H2O2-induced injury by significantly inhibiting NLRP3 inflammasome activation. In addition, LLT significantly reduced caspase1 activation, which is known to be induced by inflammasome formation, and consequently regulated the secretion of IL-1β/IL-18. We demonstrated that LLT enhances axonal elongation and synaptic connectivity against H2O2-induced injury of rat primary cortical neuron. Conclusions Together, these results demonstrate that LLT can directly protect cultured cortical neurons from H2O2-induced neuronal damage by inhibiting NLRP3 inflammasome activation and the secretion of caspase-1 and IL-1β/IL-18. Thus, our study provides new insights into the therapeutic mechanisms of LLT and suggests that the NLRP3 inflammasome could be a promising target for treating neurological diseases.

scholarly journals Chlamydia muridarumInfection of Macrophages Stimulates IL-1βSecretion and Cell Death via Activation of Caspase-1 in an RIP3-Independent Manner

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Lixiang Chen ◽  
Xue Liu ◽  
Xin Yu ◽  
Rongrong Ren ◽  
Chao Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Innate Immune ◽  
Host Cells ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Independent Manner ◽  
Chlamydia Muridarum ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Chlamydiae are Gram-negative bacteria, which replicate exclusively in the infected host cells. Infection of the host cells by Chlamydiae stimulates the innate immune system leading to an inflammatory response, which is manifested not only by secretion of proinflammatory cytokines such as IL-1βfrom monocytes, macrophages, and dendritic cells, but also possibly by cell death mediated by Caspase-1 pyroptosis. RIP3 is a molecular switch that determines the development of necrosis or inflammation. However, the involvement of RIP3 in inflammasome activation byChlamydia muridaruminfection has not been clarified. Here, we assessed the role of RIP3 in synergy with Caspase-1 in the induction of IL-1βproduction in BMDM after either LPS/ATP orChlamydia muridarumstimulation. The possibility of pyroptosis and necroptosis interplays and the role of RIP3 in IL-1βproduction duringChlamydia muridaruminfection in BMDM was investigated as well. The data indicated that RIP3 is involved in NLRP3 inflammasome activation in LPS/ATP-stimulated BMDMs but not inChlamydia muridaruminfection. Pyroptosis occurred in BMDM after LPS/ATP stimulation orChlamydia muridaruminfection. Moreover, the results also illuminated the important role of the Caspase-1-mediated pyroptosis process which does not involve RIP3. Taken together, these observations may help shed new light on details in inflammatory signaling pathways activated byChlamydia muridaruminfection.

Coptisine from Coptis chinensis blocks NLRP3 inflammasome activation by inhibiting caspase-1

2019 ◽  
Vol 147 ◽  
pp. 104348 ◽  
Author(s):  
Jiasi Wu ◽  
Yu Luo ◽  
Qing Jiang ◽  
Sheng Li ◽  
Wenge Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Coptis Chinensis ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

scholarly journals The Essential Oil of Artemisia argyi H.Lév. and Vaniot Attenuates NLRP3 Inflammasome Activation in THP-1 Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengxiao Chen ◽  
Qi Bai ◽  
Yanting Wu ◽  
Qiongzhen Zeng ◽  
Xiaowei Song ◽  
...  
Keyword(s):  
Essential Oil ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Artemisia Argyi ◽  
Nlrp3 Inflammasome Activation ◽  
Long Time

Artemisia argyi H. Lév. and Vaniot is a traditional medical herb that has been used for a long time in China and other Asian counties. Essential oil is the main active fraction of Artemisia argyi H. Lév. and Vaniot, and its anti-inflammatory potential has been observed in vitro and in vivo. Here, we found that the essential oil of Artemisia argyi H. Lév. and Vaniot (EOAA) inhibited monosodium urate (MSU)- and nigericin-induced NLRP3 inflammasome activation. EOAA suppressed caspase-1 and IL-1β processing and pyroptosis. NF-κB p65 phosphorylation and translocation were also inhibited. In addition, EOAA suppressed nigericin-induced NLRP3 inflammasome activation without blocking ASC oligomerization, suggesting that it may inhibit NLRP3 inflammasome activation by preventing caspase-1 processing. Our study thus indicates that EOAA inhibits NLRP3 inflammasome activation and has therapeutic potential against NLRP3-driven diseases.

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