scholarly journals Activation of the NLRP3 Inflammasome by Particles from the Echinococcus granulosus Laminated Layer

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Cecilia Casaravilla ◽  
Álvaro Pittini ◽  
Dominik Rückerl ◽  
Judith E. Allen ◽  
Álvaro Díaz
Keyword(s):  
Dendritic Cells ◽  
Echinococcus Granulosus ◽  
Nlrp3 Inflammasome ◽  
Soft Materials ◽  
Actin Dynamics ◽  
Inflammasome Activation ◽  
Mouse Bone Marrow ◽  
Content Type ◽  
Caspase 1 ◽  
Laminated Layer

ABSTRACT The interaction of dendritic cells and macrophages with a variety of rigid noncellular particles triggers activation of the NLRP3 inflammasome and consequent secretion of interleukin 1β (IL-1β). Noncellular particles can also be generated in the context of helminth infection, since these large pathogens often shed their outermost structures during growth and/or molting. One such structure is the massive, mucin-based, soft, flexible laminated layer (LL), which protects the larval stages of cestodes of the genus Echinococcus. We show that particles from the Echinococcus granulosus LL (pLL) trigger NLRP3- and caspase-1-dependent IL-1β in lipopolysaccharide (LPS)-primed mouse bone marrow-derived dendritic cells (BMDC). This response can be elicited by pLL too large for phagocytosis and nonetheless requires actin dynamics, Syk, and phosphatidylinositol 3-kinase (PI3K). These three requirements had already been observed in our previous study on the alteration by pLL of CD86, CD40, IL-10, and IL-12 responses to LPS in BMDC; however, we now show that these alterations are independent of NLRP3 and caspase-1. In other words, an initial interaction with particles requiring actin dynamics, Syk, and PI3K, but not phagocytosis, elicits both NLRP3-dependent and NLRP3-independent responses. Intraperitoneal injection of pLL induced IL-1β, suggesting that contact with LL materials induces IL-1β in the E. granulosus infection setting. Our results extend our understanding of NLRP3 inflammasome activation by noncellular particulate materials both to helminth-derived materials and to flexible/soft materials.

scholarly journals Haemophilus ducreyi Infection Induces Activation of the NLRP3 Inflammasome in Nonpolarized but Not in Polarized Human Macrophages

2013 ◽  
Vol 81 (8) ◽  
pp. 2997-3008 ◽  
Author(s):  
Wei Li ◽  
Barry P. Katz ◽  
Margaret E. Bauer ◽  
Stanley M. Spinola
Keyword(s):  
Nlrp3 Inflammasome ◽  
Interleukin 1 ◽  
Study Data ◽  
Human Infection ◽  
Haemophilus Ducreyi ◽  
Inflammasome Activation ◽  
Microbial Infection ◽  
Content Type ◽  
Ulcer Disease ◽  
Caspase 1

ABSTRACTRecognition of microbial infection by certain intracellular pattern recognition receptors leads to the formation of a multiprotein complex termed the inflammasome. Inflammasome assembly activates caspase-1 and leads to cleavage and secretion of the proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-18, which help control many bacterial pathogens. However, excessive inflammation mediated by inflammasome activation can also contribute to immunopathology. Here, we investigated whetherHaemophilus ducreyi, a Gram-negative bacterium that causes the genital ulcer disease chancroid, activates inflammasomes in experimentally infected human skin and in monocyte-derived macrophages (MDM). AlthoughH. ducreyiis predominantly extracellular during human infection, several inflammasome-related components were transcriptionally upregulated inH. ducreyi-infected skin. Infection of MDM with live, but not heat-killed,H. ducreyiinduced caspase-1- and caspase-5-dependent processing and secretion of IL-1β. Blockage ofH. ducreyiuptake by cytochalasin D significantly reduced the amount of secreted IL-1β. Knocking down the expression of the inflammasome components NLRP3 and ASC abolished IL-1β production. Consistent with NLRP3-dependent inflammasome activation, blocking ATP signaling, K+efflux, cathepsin B activity, and lysosomal acidification all inhibited IL-1β secretion. However, inhibition of the production and function of reactive oxygen species did not decrease IL-1β production. Polarization of macrophages to classically activated M1 or alternatively activated M2 cells abrogated IL-1β secretion elicited byH. ducreyi. Our study data indicate thatH. ducreyiinduces NLRP3 inflammasome activation via multiple mechanisms and suggest that the heterogeneity of macrophages within human lesions may modulate inflammasome activation during human infection.

scholarly journals NLRP3 Inflammasome Activation in THP-1 Target Cells Triggered by Pathogenic Naegleria fowleri

2016 ◽  
Vol 84 (9) ◽  
pp. 2422-2428 ◽  
Author(s):  
Jong-Hyun Kim ◽  
Hae-Jin Sohn ◽  
Jong-Kyun Yoo ◽  
Heekyoung Kang ◽  
Gi-Sang Seong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Macrophage ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Naegleria Fowleri ◽  
Content Type ◽  
Inflammatory Reactions ◽  
Caspase 1 ◽  
Nægleria Fowleri

Naegleria fowleri, known as the brain-eating amoeba, causes acute primary amoebic meningoencephalitis. During swimming and other recreational water activities,N. fowleritrophozoites penetrate the nasal mucosa and invade the olfactory bulbs, resulting in intense inflammatory reactions in the forebrain tissue. To investigate what kinds of inflammasome molecules are expressed in target cells due toN. fowleriinfection, human macrophage cells (THP-1 cells) were cocultured withN. fowleritrophozoites in a noncontact system, and consequently, interleukin-1β (IL-1β) production was estimated. Caspase-1 activation and IL-1β production from THP-1 cells by Western blotting and the culture supernatant by enzyme-linked immunosorbent assay analysis were observed at 3 h after cocultivation. In addition, the increased expression of ASC and NLRP3, which make up an inflammasome complex, was also observed at 3 h after cocultivation. To confirm the caspase-1 activation and IL-1β production via the NLRP3 inflammasome in THP-1 cells triggered byN. fowleritrophozoites, THP-1 cells were pretreated with several inhibitors. The inhibition assay showed that CA-074 (a cathepsin B inhibitor), glybenclamide (an NLRP3 molecule inhibitor), andN-benzyloxycarbony-Val-Ala-Asp(O-methyl)-fluoromethylketone (Z-VAD-FMK; a caspase-1 inhibitor) reduced the levels of caspase-1 activation and IL-1β production from THP-1 cells. This study suggests thatN. fowleriinfection induces the NLRP3 inflammasome, which activates caspase-1 and subsequently produces IL-1β, thus resulting in inflammation.

scholarly journals Pathogenic Fungus Microsporum canis Activates the NLRP3 Inflammasome

2013 ◽  
Vol 82 (2) ◽  
pp. 882-892 ◽  
Author(s):  
Liming Mao ◽  
Liping Zhang ◽  
Hua Li ◽  
Wei Chen ◽  
Hongbin Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nlrp3 Inflammasome ◽  
Tinea Capitis ◽  
Pathogenic Fungus ◽  
Innate Immune ◽  
Clinical Strain ◽  
Inflammasome Activation ◽  
Microsporum Canis ◽  
Invasive Infection ◽  
Content Type

ABSTRACTMicrosporum canisis a pathogenic fungus with worldwide distribution that causes tinea capitis in animals and humans.M. canisalso causes invasive infection in immunocompromised patients. To defy pathogenic fungal infection, the host innate immune system is the first line of defense. As an important arm of innate immunity, the inflammasomes are intracellular multiprotein complexes that control the activation of caspase-1, which cleaves proinflammatory cytokine pro-interleukin-1β (IL-1β) into its mature form. To determine whether the inflammasome is involved in the host defense againstM. canisinfection, we challenged human monocytic THP-1 cells and mouse dendritic cells with a clinical strain ofM. canisisolated from patients with tinea capitis. We found thatM. canisinfection triggered rapid secretion of IL-1β from both THP-1 cells and mouse dendritic cells. Moreover, by using gene-specific shRNA and competitive inhibitors, we determined thatM. canis-induced IL-1β secretion was dependent on NLRP3. The pathways proposed for NLRP3 inflammasome activation, namely, cathepsin B activity, K+efflux, and reactive oxygen species production, were all required for the inflammasome activation triggered byM. canis. Meanwhile, Syk, Dectin-1, and Card9 were found to be involved inM. canis-induced IL-1β secretion via regulation of pro-IL-1β transcription. More importantly, our data revealed thatM. canis-induced production of IL-1β was dependent on the NLRP3 inflammasomein vivo. Together, this study unveils that the NLRP3 inflammasome exerts a critical role in host innate immune responses againstM. canisinfection, and our data suggest that diseases that result fromM. canisinfection might be controlled by regulating the activation of inflammasomes.

scholarly journals Induction of Caspase-11 by Aspartyl Proteinases of Candida albicans and Implication in Promoting Inflammatory Response

2015 ◽  
Vol 83 (5) ◽  
pp. 1940-1948 ◽  
Author(s):  
Elena Gabrielli ◽  
Eva Pericolini ◽  
Eugenio Luciano ◽  
Samuele Sabbatini ◽  
Elena Roselletti ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Type I Interferon ◽  
Inflammasome Activation ◽  
Type I ◽  
Subsequent Increase ◽  
Content Type ◽  
Caspase 1 ◽  
Aspartyl Proteinases

We recently demonstrated that the secreted aspartyl proteinases (Saps), Sap2 and Sap6, ofCandida albicanshave the potential to induce the canonical activation of the NLRP3 inflammasome, leading to the secretion of interleukin-1β (IL-1β) and IL-18 via caspase-1 activation. We also observed that the activation of caspase-1 is partially independent from the NLRP3 activation pathway. In this study, we examined whether Sap2 and Sap6 are also able to activate the noncanonical inflammasome pathway in murine macrophages. Our data show that both Sap2 and Sap6 can activate caspase-11 through type I interferon (IFN) production. Caspase-11 cooperates to activate caspase-1, with a subsequent increase of IL-1β secretion. Endocytosis and internalization of Saps are required for the induction of type I IFN production, which is essential for induction of noncanonical inflammasome activation. Our study indicates a sophisticated interplay between caspase-1 and caspase-11 that connects the canonical and noncanonical pathways of inflammasome activation in response toC. albicansSaps.

scholarly journals Synergistic Costimulatory Effect of Chlamydia pneumoniae with Carbon Nanoparticles on NLRP3 Inflammasome-Mediated Interleukin-1β Secretion in Macrophages

2015 ◽  
Vol 83 (7) ◽  
pp. 2917-2925 ◽  
Author(s):  
Junji Matsuo ◽  
Shinji Nakamura ◽  
Seiji Takeda ◽  
Kasumi Ishida ◽  
Tomohiro Yamazaki ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Carbon Nanoparticles ◽  
Actin Polymerization ◽  
Chlamydia Pneumoniae ◽  
Community Acquired Pneumonia ◽  
Interleukin 1Β ◽  
Inflammasome Activation ◽  
Nlrp3 Gene ◽  
Content Type ◽  
Caspase 1

The obligate intracellular bacteriumChlamydia pneumoniaeis not only a causative agent of community-acquired pneumonia but is also associated with a more serious chronic disease, asthma, which might be exacerbated by air pollution containing carbon nanoparticles. Although a detailed mechanism of exacerbation remains unknown, the proinflammatory cytokine interleukin-1β (IL-1β) is a critical player in the pathogenesis of asthma.C. pneumoniaeinduces IL-1β in macrophages via NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation and Toll-like receptor 2/4 (TLR2/4) stimulation. Carbon nanoparticles, such as carbon nanotubes (CNTs), can also evoke the NLRP3 inflammasome to trigger IL-1β secretion from lipopolysaccharide-primed macrophages. This study assessed whether costimulation ofC. pneumoniaewith CNTs synergistically enhanced IL-1β secretion from macrophages, and determined the molecular mechanism involved. Enhanced IL-1β secretion fromC. pneumoniae-infected macrophages by CNTs was dose and time dependent. Transmission electron microscopy revealed thatC. pneumoniaeand CNTs were engulfed concurrently by macrophages. Inhibitors of actin polymerization or caspase-1, a component of the inflammasome, significantly blocked IL-1β secretion. Gene silencing using small interfering RNA (siRNA) targeting the NLRP3 gene also abolished IL-1β secretion. Other inhibitors (K+efflux inhibitor, cathepsin B inhibitor, and reactive oxygen species-generating inhibitor) also blocked IL-1β secretion. Taken together, these findings demonstrated that CNTs synergistically enhanced IL-1β secretion fromC. pneumoniae-infected macrophages via the NLRP3 inflammasome and caspase-1 activation, providing novel insight into our understanding of howC. pneumoniaeinfection can exacerbate asthma.

scholarly journals Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Do-Wan Shim ◽  
Hyo-Joung Cho ◽  
Inhwa Hwang ◽  
Taek-Yeol Jung ◽  
Hyun-Seok Kim ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Specific Inhibitor ◽  
Retrograde Transport ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
Mouse Bone Marrow ◽  
Caspase 1 ◽  
Nicotinamide Mononucleotide ◽  
Nlrp3 Inflammasome Activation

Nicotinamide adenine dinucleotide (NAD+) is an important cofactor in many redox and non-redox NAD+-consuming enzyme reactions. Intracellular NAD+ level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD+ depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages. NAD+-depleted mouse bone marrow-derived macrophages (BMDMs) exhibited similar levels of proinflammatory cytokine production in response to LPS or poly (I:C) stimulation compared with untreated cells. Instead, FK866 facilitated robust caspase-1 activation in BMDMs in the presence of NLRP3-activating signals such as ATP and nigericin, a potassium ionophore. However, this FK866-mediated caspase-1 activation was completely abolished in Nlrp3-deficient macrophages. FK866 plus nigericin stimulation caused an NLRP3-dependent assembly of inflammasome complex. In contrast, restoration of NAD+ level by supplementation with nicotinamide mononucleotide abrogated the FK866-mediated caspase-1 cleavage. FK866 did not induce or increase the expression levels of NLRP3 and interleukin (IL)-1β but drove mitochondrial retrograde transport into the perinuclear region. FK866-nigericin-induced mitochondrial transport is critical for caspase-1 cleavage in macrophages. Consistent with the in vitro experiments, intradermal coinjection of FK866 and ATP resulted in robust IL-1β expression and caspase-1 activation in the skin of wild-type, but not Nlrp3-deficient mice. Collectively, our data suggest that NAD+ depletion provides a non-transcriptional priming signal for NLRP3 activation via mitochondrial perinuclear clustering, and aging-associated NAD+ decline can trigger NLRP3 inflammasome activation in ATP-rich environments.

scholarly journals Methotrexate enhances antigen presentation and maturation of tumour antigen-loaded dendritic cells through NLRP3 inflammasome activation: a strategy for dendritic cell-based cancer vaccine

2021 ◽  
Vol 13 ◽  
pp. 175883592098705
Author(s):  
Gao-Na Shi ◽  
Min Hu ◽  
Chengjuan Chen ◽  
Junmin Fu ◽  
Shuai Shao ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Nlrp3 Inflammasome ◽  
Tumour Antigen ◽  
Inflammasome Activation ◽  
Antigen Uptake ◽  
Nlrp3 Inflammasome Activation ◽  
Dc Maturation

Background: Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in adaptive cell-mediated immunity by priming and activating T cells against specific tumour and pathogenic antigens. Methotrexate (MTX), a folate derivative, functions as an immunoregulatory agent. However, the possible effect of MTX on tumour antigen-loaded DCs has not yet been investigated. Methods: We analysed the effect of MTX on the maturation and function of DCs along with tumour cell lysates (TCLs). Using bone marrow-derived DCs, we investigated the effect of MTX combined TCL-loaded DCs on T cells priming and proliferation. We also tested the anti-tumour immune effect on DCs when treated with MTX and/or TCL in vivo. Results: MTX combined with TCL not only enhanced DC maturation and stimulated cytokine release but also promoted CD8+ T cell activation and proliferation. The latter was associated with increased tumour antigen uptake and cross-presentation to T cells. Mechanistically, DC maturation and antigen presentation were partly modulated by NLRP3 inflammasome activation. Furthermore, immunisation of mice with MTX and TCL-pulsed DCs before a tumour challenge significantly delayed tumour onset and retarded its growth. This protective effect was due to priming of IFN-γ releasing CD8+ T cells and enhanced killing of tumour cells by cytotoxic T lymphocytes isolated from these immunised mice. Conclusion: MTX can function as a potent adjuvant in DC vaccines by increasing antigen presentation and T cell priming. Our findings provide a new strategy for the application of DC-based anti-tumour immunotherapy.

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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