scholarly journals MCL Plays an Anti-Inflammatory Role inMycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qingwen Zhang ◽  
Xinru Jiang ◽  
Weigang He ◽  
Kailin Wei ◽  
Jinxia Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inhibitory Effect ◽  
Drug Candidate ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation

Mycobacterium tuberculosis(Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1βand TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

scholarly journals Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Chen Dai ◽  
Bin Liu ◽  
Bibo Peng ◽  
Bo Qu ◽  
Jiezhi Lin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Motor Function ◽  
Nlrp3 Inflammasome ◽  
Neuronal Damage ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Cord Injury

Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI.Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage.Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression.Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.

scholarly journals Juglone Suppresses LPS-induced Inflammatory Responses and NLRP3 Activation in Macrophages

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3104 ◽  
Author(s):  
Nam-Hun Kim ◽  
Hong-Ki Kim ◽  
Ji-Hak Lee ◽  
Seung-Il Jo ◽  
Hye-Min Won ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
No Production ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Inflammatory Cytokine Production ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome has been implicated in a variety of diseases, including atherosclerosis, neurodegenerative diseases, and infectious diseases. Thus, inhibitors of NLRP3 inflammasome have emerged as promising approaches to treat inflammation-related diseases. The aim of this study was to explore the effects of juglone (5-hydroxyl-1,4-naphthoquinone) on NLRP3 inflammasome activation. The inhibitory effects of juglone on nitric oxide (NO) production were assessed in lipopolysaccharide (LPS)-stimulated J774.1 cells by Griess assay, while its effects on reactive oxygen species (ROS) and NLRP3 ATPase activity were assessed. The expression levels of NLRP3, caspase-1, and pro-inflammatory cytokines (IL-1β, IL-18) and cytotoxicity of juglone in J774.1 cells were also determined. Juglone was non-toxic in J774.1 cells when used at 10 μM (p < 0.01). Juglone treatment inhibited the production of ROS and NO. The levels of NLRP3 and cleaved caspase-1, as well as the secretion of IL-1β and IL-18, were decreased by treatment with juglone in a concentration-dependent manner. Juglone also inhibited the ATPase activities of NLRP3 in LPS/ATP-stimulated J774.1 macrophages. Our results suggested that juglone could inhibit inflammatory cytokine production and NLRP3 inflammasome activation in macrophages, and should be considered as a therapeutic strategy for inflammation-related diseases.

scholarly journals Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Liu Ye ◽  
Qi Zeng ◽  
Maoyao Ling ◽  
Riliang Ma ◽  
Haishao Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lung Injury ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Ventilator Induced Lung Injury ◽  
Nlrp3 Inflammasome Activation

RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

scholarly journals Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Ma ◽  
Guoyang Li ◽  
Minghui Qi ◽  
Wei Jiang ◽  
Rongbin Zhou
Keyword(s):  
Inflammatory Response ◽  
Allergic Asthma ◽  
Nlrp3 Inflammasome ◽  
Treatment Options ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation ◽  
Dust Mite ◽  
New Treatment ◽  
Inflammasome Activity

Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1β in alveolar macrophages (AMs). Using Nlrp3-mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.

scholarly journals Role of Lysosomes in Silica-Induced Inflammasome Activation and Inflammation in Absence of MARCO

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Rupa Biswas ◽  
Raymond F. Hamilton ◽  
Andrij Holian
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Scavenger Receptor ◽  
Acid Sphingomyelinase ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
The Difference ◽  
Silica Treatment

MARCO is the predominant scavenger receptor for recognition and binding of silica particles by alveolar macrophages (AM). Previously, it was shown that mice null for MARCO have a greater inflammatory response to silica, but the mechanism was not described. The aim of this study was to determine the relationship between MARCO and NLRP3 inflammasome activity. Silica increased NLRP3 inflammasome activation and release of the proinflammatory cytokine, IL-1β, to a greater extent in MARCO−/−AM compared to wild type (WT) AM. Furthermore, in MARCO−/−AM there was greater cathepsin B release from phagolysosomes, Caspase-1 activation, and acid sphingomyelinase activity compared to WT AM, supporting the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation. The difference in sensitivity to LMP appears to be in cholesterol recycling since increasing cholesterol in AM by treatment with U18666A decreased silica-induced NLRP3 inflammasome activation, and cells lacking MARCO were less able to sequester cholesterol following silica treatment. Taken together, these results demonstrate that MARCO contributes to normal cholesterol uptake in macrophages; therefore, in the absence of MARCO, macrophages are more susceptible to a greater inflammatory response by particulates known to cause NLRP3 inflammasome activation and the effect is due to increased LMP.

scholarly journals Defective endosome-TGN retrograde transport promotes NLRP3 inflammasome activation

2021 ◽  
Author(s):  
Romeo Ricci ◽  
Zhirong Zhang ◽  
Li Ran ◽  
Rossella Venditti ◽  
Zengzhen Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Retrograde Transport ◽  
Serum Levels ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Potassium Efflux ◽  
Nlrp3 Inflammasome Activation ◽  
Broad Variety

Abstract Inflammasome complexes are pivotal in the innate immune response to pathogens and other danger signals. The NLRP3 inflammasome is activated in response to a broad variety of cellular stressors. Most of the stimuli act in a potassium efflux-dependent manner but a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill-defined. Here we show that NLRP3 activators disrupt endosome-TGN retrograde transport (ETRT) and lead to localization of NLRP3 to endosomal vesicles. Genetic and pharmacologic perturbation of ETRT leads to accumulation of phosphoinositol-4-phosphate (PI4P) in endosomes to which NLRP3 is recruited. Disruption of ETRT potentiates NLRP3 inflammasome activation in murine and human macrophages in vitro. Mice with defects in ETRT in the myeloid compartment are more susceptible to LPS-induced sepsis showing enhanced mortality and IL-1β serum levels as compared to control animals. Our study thus uncovers that changes in endocytic trafficking mediate NLRP3-dependent inflammatory responses.

Mechanosensitive TRPV4 is required for crystal-induced inflammation

2021 ◽  
pp. annrheumdis-2021-220295
Author(s):  
Zhou Lan ◽  
Lvyi Chen ◽  
Jing Feng ◽  
Zili Xie ◽  
Zhiyong Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Gouty Arthritis ◽  
Inflammasome Activation ◽  
Acute Gout ◽  
Human Pbmcs ◽  
Nlrp3 Inflammasome Activation ◽  
Gout Flares

Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and Trpv4eGFP mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca2+ imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1β which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.

scholarly journals Defective endosome-TGN retrograde transport promotes NLRP3 inflammasome activation

2021 ◽  
Author(s):  
Zhirong ZHANG ◽  
Li RAN ◽  
Rossella Venditti ◽  
Zengzhen Liu ◽  
Annette Schurmann ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Retrograde Transport ◽  
Serum Levels ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Potassium Efflux ◽  
Nlrp3 Inflammasome Activation ◽  
Broad Variety

Inflammasome complexes are pivotal in the innate immune response to pathogens and other danger signals. The NLRP3 inflammasome is activated in response to a broad variety of cellular stressors. Most of the stimuli act in a potassium efflux-dependent manner but a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill-defined. Here we show that NLRP3 activators disrupt endosome-TGN retrograde transport (ETRT) and lead to localization of NLRP3 to endosomal vesicles. Genetic and pharmacologic perturbation of ETRT leads to accumulation of phosphoinositol-4-phosphate (PI4P) in endosomes to which NLRP3 is recruited. Disruption of ETRT potentiates NLRP3 inflammasome activation in murine and human macrophages in vitro. Mice with defects in ETRT in the myeloid compartment are more susceptible to LPS-induced sepsis showing enhanced mortality and IL-1β serum levels as compared to control animals. Our study thus uncovers that changes in endocytic trafficking mediate NLRP3-dependent inflammatory responses.

scholarly journals A potential role of microvesicle-containing miR-223/142 in lung inflammation

Thorax ◽  
2019 ◽  
Vol 74 (9) ◽  
pp. 865-874 ◽  
Author(s):  
Duo Zhang ◽  
Heedoo Lee ◽  
Xiaoyun Wang ◽  
Michael Groot ◽  
Lokesh Sharma ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Intratracheal Instillation ◽  
Lavage Fluid ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Membrane Budding

BackgroundUncontrolled lung inflammation is one of the prominent features in the pathogenesis of lung infection- associated acute lung injury (ALI). Microvesicles (MVs) are extracellular nanovesicles that are generated via direct membrane budding.MethodsBronchoalveolar lavage fluid (BALF) samples were collected from mice with or without intratracheal lipopolysaccharide (LPS) instillation. BALF MVs were characterised and MV-containing microRNA (miRNA) profiles were assessed and confirmed. Secretion and function of MV-containing miR-223/142 (MV-miR-223/142) were analysed in vivo.ResultsIn BALF, MVs are mainly derived from macrophages in response to LPS. After intratracheal instillation (i.t.) of LPS or Klebsiella pneumoniae, MV-containing miR-223/142 are dramatically induced in both BALF and serum. Mechanistically, miRNA 3′ end uridylation mediates the packing of miR-223/142 into MVs. To investigate the functional role of MV-miR-223/142, we loaded miR-223/142 mimics into unstimulated MVs and delivered them into the murine lungs via i.t. The miR-223/142 mimics-enriched MVs selectively targeted lung macrophages and suppressed the inflammatory lung responses that were triggered by LPS or K. pneumoniae. Mechanistically, miR-223 and miR-142 synergistically suppress Nlrp3 inflammasome activation in macrophages via inhibition of Nlrp3 and Asc, respectively.ConclusionsIn the pathogenesis of lung macrophage-mediated inflammatory responses, MV-miR-223/142 secretion is robustly enhanced and detectable in BALF and serum. Furthermore, restoration of intracellular miR-223/142 via vesicle-mediated delivery suppresses macrophage activation and lung inflammation via inhibition of Nlrp3 inflammasome activation.

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