scholarly journals Topical Application of the Antimicrobial Agent Triclosan Induces NLRP3 Inflammasome Activation and Mitochondrial Dysfunction

2020 ◽  
Vol 176 (1) ◽  
pp. 147-161
Author(s):  
Lisa M Weatherly ◽  
Hillary L Shane ◽  
Sherri A Friend ◽  
Ewa Lukomska ◽  
Rachel Baur ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dysfunction ◽  
Allergic Disease ◽  
Nlrp3 Inflammasome ◽  
Immune Cell ◽  
Skin Tissue ◽  
Mitochondrial Morphology ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Inflammatory Monocytes

Abstract 5-Chloro-2-(2,4-dichlorophenoxy)phenol (triclosan) is an antimicrobial chemical widely used in consumer household and clinical healthcare products. Human and animal studies have associated triclosan exposure with allergic disease. Mechanistic studies have identified triclosan as a mitochondrial uncoupler; recent studies suggest that mitochondria play an important role in immune cell function and are involved in activation of the NLRP3 inflammasome. In this study, early immunological effects were evaluated via NLRP3 activation following dermal triclosan application in a BALB/c murine model. These investigations revealed rapid caspase-1 activation and mature IL-1β secretion in the skin and draining lymph nodes (dLNs) after 1.5% and 3% triclosan exposure. Correspondingly, pro-Il-1b and S100a8 gene expression increased along with extracellular ATP in the skin. Peak gene expression of chemokines associated with caspase-1 activation occurred after 2 days of exposure in both skin tissue and dLNs. Phenotypic analysis showed an increase in neutrophils and macrophages in the dLN and myeloid and inflammatory monocytes in the skin tissue. Triclosan also caused mitochondrial dysfunction shown through effects on mitochondrial reactive oxygen species, mass, mitochondrial membrane potential, and mitochondrial morphology. These results indicate that following triclosan exposure, activation of the NLRP3 inflammasome occurs in both the skin tissue and dLNs, providing a possible mechanism for triclosan’s effects on allergic disease and further support a connection between mitochondrial involvements in immunological responses.

Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury

2015 ◽  
Vol 308 (8) ◽  
pp. F857-F866 ◽  
Author(s):  
Yibo Zhuang ◽  
Marchella Yasinta ◽  
Caiyu Hu ◽  
Min Zhao ◽  
Guixia Ding ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Cell Apoptosis ◽  
Kidney Diseases ◽  
Mitochondrial Morphology ◽  
Tubular Injury ◽  
Chronic Kidney Diseases ◽  
Caspase 1 ◽  
Cytokine Cascade ◽  
Renal Tubular

Proteinuria is involved in the development of tubular lesions and in the progressive loss of renal function in chronic kidney diseases via uncertain mechanisms. Growing evidence suggests a pathogenic role of mitochondrial dysfunction in chronic kidney diseases. Therefore, the present study aimed to define the roles of mitochondria in proteinuria-induced renal tubular injury and their underlying mechanisms. Using the albumin-overload mouse model, we observed severe tubular structure damage and striking tubular cell apoptosis. Furthermore, tubular epithelial cells displayed a loss of E-cadherin expression and gained expression of α-smooth muscle actin and vimentin, indicating a cellular phenotypic alteration. Strikingly, these albumin overload-induced abnormalities were robustly blocked by a mitochondrial SOD2 mimic, Mn(III) tetrakis (4-benzoic acid)porphyrin chloride (MnTBAP). In agreement with these results, we observed a marked change in mitochondrial morphology accompanied by mitochondrial cytochrome c release and a copy number reduction of mitochondrial DNA. These alterations were largely reversed by MnTBAP, suggesting a key role for mitochondria-derived oxidative stress in mediating the albumin effect on mitochondrial dysfunction and subsequent tubular injury. Moreover, the NOD-like receptor family, pyrin domain-containing 3 (NLRP3)/caspase-1/cytokine cascade was activated in the kidney by albumin overload and was entirely abolished by MnTBAP. In albumin-treated mouse proximal tubular cells, albumin directly induced ROS production, mitochondrial dysfunction, NLRP3/caspase-1/cytokine cascade activation, cell apoptosis, and cellular phenotypic transition. Similar to our in vivo results, treatment with either MnTBAP or cyclosporin A, a mitochondrial permeability transition pore inhibitor, remarkably attenuated these abnormalities in cells. Taken together, these novel findings demonstrate a potential role for the mitochondrial dysfunction/NLRP3 inflammasome axis in the pathogenesis of proteinuria-induced renal tubular injury.

scholarly journals Sweroside Prevents Non-Alcoholic Steatohepatitis by Suppressing Activation of the NLRP3 Inflammasome

2020 ◽  
Vol 21 (8) ◽  
pp. 2790 ◽  
Author(s):  
Gabsik Yang ◽  
Joo Hyeon Jang ◽  
Sung Wook Kim ◽  
Sin-Hee Han ◽  
Kyung-Ho Ma ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Immune Cell ◽  
Inflammasome Activation ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Caspase 1 ◽  
Triglyceride Accumulation ◽  
Nlrp3 Inflammasome Activation ◽  
Primary Mouse

Non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease, is characterized as steatosis and inflammation in the liver. NLRP3 inflammasome activation is associated with NASH pathology. We hypothesized that suppressing the NLRP3 inflammasome could be effective in preventing NASH. We searched substances that could inhibit the activation of the NLRP3 inflammasome and identified sweroside as an NLRP3 inhibitor. We investigated whether sweroside can be applied to prevent the pathological symptoms associated with NASH in a methionine–choline-deficient (MCD) diet-induced NASH mouse model. The activation of the NLRP3 inflammasome was determined by detecting the production of caspase-1 and IL-1β from pro-caspase-1 and pro-IL-1β in primary mouse macrophages and mouse liver. In a NASH model, mice were fed an MCD diet for two weeks with daily intraperitoneal injections of sweroside. Sweroside effectively inhibited NLRP3 inflammasome activation in primary macrophages as shown by a decrease in IL-1β and caspase-1 production. In a MCD diet-induced NASH mouse model, intraperitoneal injection of sweroside significantly reduced serum aspartate transaminase and alanine transaminase levels, hepatic immune cell infiltration, hepatic triglyceride accumulation, and liver fibrosis. The improvement of NASH symptoms by sweroside was accompanied with its inhibitory effects on the hepatic NLRP3 inflammasome as hepatic IL-1β and caspase-1 were decreased. Furthermore, sweroside blocked de novo synthesis of mitochondrial DNA in the liver, contributing to suppression of the NLRP3 inflammasome. These results suggest that targeting the NLRP3 inflammasome with sweroside could be beneficially employed to improve NASH symptoms.

Inflammasome and Autophagy Activation In Symptomatic Multiple Myeloma Could Predict Response To Thalidomide-Based Chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3131-3131
Author(s):  
Fernando V Pericole ◽  
Adriana Silva Santos Duarte ◽  
Mariana Lazarini ◽  
Sara Teresinha Olalla Saad
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Inflammation ◽  
Clinical Data ◽  
Conflicts Of Interest ◽  
Inflammatory Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Inflammatory Monocytes

Abstract The inflammasome is a protein complex activated by signals of cellular danger to trigger the innate immune defenses through the maturation of proinflammatory cytokines such as interleukin (IL)1β and IL18. Inflammasomes consist of pattern-recognition sensors (NLR family), adaptors (ASC), and effectors (caspase 1). IL1β initiates feedback loops through the IL1R-MyD88-NFκB pathway. Inflammasome activation promotes adaptive responses and limits reactive oxygen species (ROS) production. Autophagy is a cytoprotective pathway by which the cell sequesters damaged proteins and organelles for lysosomal degradation. The inflammasome is negatively regulated by autophagy and inflammasome activates autophagy. Inflammasome activity may play an important role in several nonmicrobial diseases with chronic inflammation, such as obesity, type 2 diabetes and cancer. We collected a cohort of diagnostic samples of total bone marrow (BM) from 31 MM patients, 3 plasma cell leukemia (PCL) patients and 9 healthy bone marrow donors (HD), together with clinical data. Four smoldering MM, 27 symptomatic MM and 3 PCL (2 primary and 1 secondary) were included. According to ISS, six patients were ISS I, 9 patients were ISS II and 16 were ISS III. We also stratified 18 of our symptomatic MM into groups according to response (CR/VGPR, PR, SD/PD). The offered treatment was thalidomide-based triplets. Essential genes from inflammasome (NLRP3, PYCARD, CASP1), pro-inflammatory interleukins (IL1B, IL18) and autophagy (BECN1, SQSTM1, MAP1LC3B) were verified by q-PCR. Gene expression was compared among subgroups and correlated with clinical data. CASP1 and PYCARD were increased in MM compared with HD, without differences among ISS subgroups. In PCL cases, CASP1 and PYCARD had lower expression when compared with MM, but did not differ from HD, confirming that PCL did not have inflammasome activation as MM did. NLRP3 was not different among all diagnostic subgroups. IL18 had decreased expression in PCL patients, compared with HD and MM. IL1B was not different among subgroups. PCL and MM had higher BECN1 expression compared with HD and these differences were also highlighted among ISS subgroups. SQSTM1 had increased expression in PCL, compared with HD and MM, but MM did not differ from HD. MAP1LC3B gene expression was similar among groups. A positive correlation was observed between CASP1 and PYCARD, IL1B and IL18, and between the three autophagic genes (BECN1, SQSTM1 and MAP1LC3B) as expected. BECN1 also correlated with IL1B and with CASP1; CASP1 and PYCARD correlated with BECN1 and SQSTM1, reinforcing the relation between autophagy and inflammasome. When the clinical data were analyzed, monocyte counts correlated with CASP1 and PYCARD; beta-2-microglobulin levels correlated with CASP1 and with NLRP3 and, finally, leukocyte and neutrophil counts correlated with IL1B, BECN1 and SQSTM1 BM expression levels. Analyzing response to thalidomide-based first line chemotherapy, VGPR/CR responders showed higher diagnostic NLRP3 expression (unpaired t test, P=0.03). The intricate interplay between autophagy and inflammasome has only recently been elucidated. Multiple myeloma is a B-cell neoplasm with great dependence of BM microenvironment. Inflammatory cells, especially monocytes and macrophages, are the main inflammasome activators, reducing ROS in the BM microenvironment. Autophagy is essential for plasmocytes, due to their high levels of intracellular proteins. Basal levels of autophagy in myeloma are high and are upregulated in response to ER stress and proteasome inhibition, protecting myeloma cells against apoptosis. Our results confirm the essential role of autophagy activation in myeloma. Interestingly, inflammasome activation in our cohort predicted a better response to thalidomide-based regimens and could be a novel response biomarker. Reinforcing our theory, recently thalidomide was described as an inhibitor of caspase 1 activation. Chronic inflammation is an established cancer hallmark and its role in myeloma pathogenesis seems to be important through inflammasome and autophagy dysfunction during disease progression, possibly creating dependency loops between inflammatory monocytes and neoplastic plasmocyte within the BM microenvironment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

2019 ◽  
Vol 17 (12) ◽  
pp. 1245-1256 ◽  
Author(s):  
Yuting Jin ◽  
Changyong Li ◽  
Dongwei Xu ◽  
Jianjun Zhu ◽  
Song Wei ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Inflammatory Injury ◽  
Notch1 Signaling ◽  
Caspase 1 ◽  
Hepatocellular Damage ◽  
Hepatocellular Apoptosis

AbstractNotch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

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 miR-29a-5p Alleviates Traumatic Brain Injury (TBI)-Induced Permeability Disruption Via Regulating NLRP3 Pathway

2021 ◽  
Author(s):  
Aijun Zhang ◽  
Youming Lu ◽  
Lei Yuan ◽  
Pengqi Zhang ◽  
Dongdong Zou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Endothelial Cell ◽  
Brain Injury ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Promising Strategy ◽  
Pathway Activation ◽  
Nlrp3 Expression

Abstract Blood-brain barrier (BBB) dysfunction is presented during traumatic brain injury (TBI) and is dependent upon the activation of the NLRP3/Caspase-1 inflammasome pathway. MicroRNA (miRNA) was proved to inhibit signaling pathway activation by targeting gene expression and we predicated in the database that miR-29a targets to NLRP3. Herein, this study aims to define the regulating role of miR-29a in NLRP3 expression and NLRP3/Caspase-1 inflammasome activation in TBI-induced BBB dysfunction. Our results indicated that miR-29a-5p alleviates TBI-induced the increased permeability of endothelial cell and BBB via suppressing NLRP3 expression and NLRP3/Caspase-1 inflammasome activation, providing a promising strategy for relieving TBI via inhibiting NLRP3/Caspase-1 inflammasome activation.

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