scholarly journals P2Y2 Receptor Induces L. amazonensis Infection Control in a Mechanism Dependent on Caspase-1 Activation and IL-1β Secretion

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Maria Luiza Thorstenberg ◽  
Monique Daiane Andrade Martins ◽  
Vanessa Figliuolo ◽  
Claudia Lucia Martins Silva ◽  
Luiz Eduardo Baggio Savio ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Cutaneous Leishmaniasis ◽  
Nlrp3 Inflammasome ◽  
Parasite Load ◽  
Inflammasome Activation ◽  
P2y2 Receptor ◽  
Wild Type ◽  
Extracellular Medium ◽  
Caspase 1 ◽  
Infected Cells

Leishmaniasis is a neglected tropical disease caused by an intracellular parasite of the genus Leishmania. Damage-associated molecular patterns (DAMPs) such as UTP and ATP are released from infected cells and, once in the extracellular medium, activate P2 purinergic receptors. P2Y2 and P2X7 receptors cooperate to control Leishmania amazonensis infection. NLRP3 inflammasome activation and IL-1β release resulting from P2X7 activation are important for outcomes of L. amazonensis infection. The cytokine IL-1β is required for the control of intracellular parasites. In the present study, we investigated the involvement of the P2Y2 receptor in the activation of NLRP3 inflammasome elements (caspase-1 and 11) and IL-1β secretion during L. amazonensis infection in peritoneal macrophages as well as in a murine model of cutaneous leishmaniasis. We found that 2-thio-UTP (a selective P2Y2 agonist) reduced parasite load in L. amazonensis-infected murine macrophages and in the footpads and lymph nodes of infected mice. The antiparasitic effects triggered by P2Y2 activation were not observed when cells were pretreated with a caspase-1 inhibitor (Z-YVAD-FMK) or in macrophages from caspase-1/11 knockout mice (CASP-1,11−/−). We also found that UTP treatment induced IL-1β secretion in wild-type (WT) infected macrophages but not in cells from CASP-1,11−/− mice, suggesting that caspase-1 activation by UTP triggers IL-1β secretion in L. amazonensis-infected macrophages. Infected cells pretreated with IL-1R antagonist did not show reduced parasitic load after UTP and ATP treatment. Our in vivo experiments also showed that intralesional UTP treatment reduced both parasite load (in the footpads and popliteal lymph nodes) and lesion size in wild-type (WT) and CASP-11−/− but not in CASP-1,11−/− mice. Taken together, our findings suggest that P2Y2R activation induces CASP-1 activation and IL-1β secretion during L. amazonensis infection. IL-1β/IL-1R signaling is crucial for P2Y2R-mediated protective immune response in an experimental model of cutaneous leishmaniasis.

scholarly journals Mul1 suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc

2019 ◽  
Author(s):  
June-Hyung Kim ◽  
Yunjong Lee ◽  
Gee Young Suh ◽  
Yun-Song Lee
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Raw264.7 Cells ◽  
Inflammasome Activation ◽  
Wild Type ◽  
Ubiquitin Protein Ligase ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
In The Wild ◽  
Excessive Inflammatory Response

AbstractActivation of the Nlrp3 inflammasome consisting of three major components, Nlrp3, Asc, and pro-caspase-1, results in the activation of caspase-1 and subsequent proteolytic cleavage of pro-IL-1β and pro-IL-18. To avoid excessive inflammatory response, the Nlrp3 inflammasome has to be precisely controlled. In this study, we show that the mouse mitochondrial E3 ubiquitin protein ligase (Mul1) suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc. In J774A.1 cells, Mul1 overexpression attenuated Nlrp3 activation, whereas Mul1 knockdown augmented Nlrp3 activation in terms of IL-1β secretion and cleavage of pro-caspase-1 and pro-IL-1β. Mul1 interacted with Asc, and ubiquitinated it at K21, K22, K26, and K55 residues, in a K48-linked manner, leading to proteasomal degradation. Convincingly, Mul1-mediated suppression of Nlrp3 activation was inhibited by K21R-, K22R-, K26R-, K52R-Asc mutants in RAW264.7 cells, when compared with the wild-type Asc. Furthermore, Aim2 inflammasome activation was also inhibited by Mul1 in the wild-type Asc-, but not in mutant Asc-expressing RAW264.7 cells. Taken together, these data suggest that Mul1 suppresses Nlrp3 inflammasome activation, through Asc ubiquitination and degradation.

scholarly journals Role of Annexin A1 in NLRP3 Inflammasome Activation in Murine Neutrophils

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 121
Author(s):  
José Marcos Sanches ◽  
Rebeca D. Correia-Silva ◽  
Gustavo H. B. Duarte ◽  
Anna Maria A. P. Fernandes ◽  
Salvador Sánchez-Vinces ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Nlrp3 Inflammasome ◽  
Cell Stress ◽  
Lipid Biomarkers ◽  
Inflammasome Activation ◽  
Annexin A1 ◽  
Wild Type ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

This study evaluated the role of endogenous and exogenous annexin A1 (AnxA1) in the activation of the NLRP3 inflammasome in isolated peritoneal neutrophils. C57BL/6 wild-type (WT) and AnxA1 knockout mice (AnxA1-/-) received 0.3% carrageenan intraperitoneally and, after 3 h, the peritoneal exudate was collected. WT and AnxA1-/- neutrophils were then stimulated with lipopolysaccharide, followed by the NLRP3 agonists nigericin or ATP. To determine the exogenous effect of AnxA1, the neutrophils were pretreated with the AnxA1-derived peptide Ac2-26 followed by the NLRP3 agonists. Ac2-26 administration reduced NLRP3-derived IL-1β production by WT neutrophils after nigericin and ATP stimulation. However, IL-1β release was impaired in AnxA1-/- neutrophils stimulated by both agonists, and there was no further impairment in IL-1β release with Ac2-26 treatment before stimulation. Despite this, ATP- and nigericin-stimulated AnxA1-/- neutrophils had increased levels of cleaved caspase-1. The lipidomics of supernatants from nigericin-stimulated WT and AnxA1-/- neutrophils showed potential lipid biomarkers of cell stress and activation, including specific sphingolipids and glycerophospholipids. AnxA1 peptidomimetic treatment also increased the concentration of phosphatidylserines and oxidized phosphocholines, which are lipid biomarkers related to the inflammatory resolution pathway. Together, our results indicate that exogenous AnxA1 negatively regulates NLRP3-derived IL-1β production by neutrophils, while endogenous AnxA1 is required for the activation of the NLRP3 machinery.

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.

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.

scholarly journals Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity

2021 ◽  
Vol 5 (5) ◽  
pp. 1523-1534
Author(s):  
Johan Courjon ◽  
Océane Dufies ◽  
Alexandre Robert ◽  
Laurent Bailly ◽  
Cédric Torre ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Myeloid Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Molecular Pattern ◽  
Nlrp3 Inflammasome Activation ◽  
Healthy Donors ◽  
Activation Potential ◽  
Key Factor ◽  
Pathogen Associated Molecular Pattern

Abstract Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient’s evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.

scholarly journals NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong-Su Park ◽  
Yao Lu ◽  
Kannupriya Pandey ◽  
GuanQun Liu ◽  
Yan Zhou
Keyword(s):  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Ns1 Protein ◽  
Structural Protein ◽  
Caspase 1 ◽  
C Terminus

Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1β) production is one of the crucial responses in innate immunity upon infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular proteins. Among host proteins involved, we identified tripartite motif-containing protein 25 (TRIM25) as a positive regulator of porcine NLRP3 inflammasome-mediated IL-1β production. TRIM25 achieved this function by enhancing the pro-caspase-1 interaction with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1β signaling, while it is repressed by IAV NS1 protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.

Psidium guajava Flavonoids Prevent NLRP3 Inflammasome Activation and Alleviate the Pancreatic Fibrosis in a Chronic Pancreatitis Mouse Model

2021 ◽  
Vol 49 (08) ◽  
pp. 2001-2015
Author(s):  
Guixian Zhang ◽  
Liming Tang ◽  
Hongbin Liu ◽  
Dawei Liu ◽  
Manxue Wang ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Psidium Guajava ◽  
Pancreatic Fibrosis ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Chronic pancreatitis (CP) is a multifactorial, inflammatory syndrome characterized by acinar atrophy and fibrosis. Activation of NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome is a central mediator of multiple chronic inflammatory responses and chronic fibrosis including pancreatic fibrosis in CP. The Psidium guajavaleaf is widely used in traditional medicine for the treatment of chronic inflammation, but the anti-inflammatory effect of Psidium guajavaleaf on CP has not yet been revealed. In this study, we investigated whether the extract of total flavonoids from Psidium guajava leaves (TFPGL) plays a therapeutic mechanism on CP through NLRP3 inflammasome signaling pathway in a mouse CP model. The H&E and acid-Sirius red staining indicted that TFPGL attenuated the inflammatory cell infiltration and fibrosis significantly. The results of immunohistological staining, western blot and RT-qPCR showed that the expressions of NLRP3 and caspase-1 were significantly increased in the CP model group, while TFPGL significantly decreased the NLRP3 and caspase-1 expression at both the gene and protein levels. Moreover, ELISA assay was used to examine the levels of NLRP3 inflammasome target genes, such as caspase-1, IL-1[Formula: see text] and IL-18. We found that TFPGL treatment decreased the expression of caspase-1, IL-1[Formula: see text] and IL-18, which is critical for the NLRP3 inflammasome signaling pathway and inflammation response significantly. These results demonstrated that TFPGL attenuated pancreatic inflammation and fibrosis via preventing NLRP3 inflammasome activation and TFPGL can be used as a potential therapeutic agent for CP.

scholarly journals Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Leng ◽  
Yingjie Zhang ◽  
Xinran Liu ◽  
Zhen Zhang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Inflammasome Activation ◽  
Astragaloside Iv ◽  
Caspase 1 ◽  
Endothelial Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

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