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Inflammasome phosphorylation

Takuya Wakamatsu, Suguru Yamamoto, Toru Ito, Yoko Sato, Koji Matsuo, Yoshimitsu Takahashi, Yoshikatsu Kaneko, Shin Goto, Junichiro James Kazama, Fumitake Gejyo, Ichiei Narita
In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay...
March 15, 2018: Toxins
John R Apps, Gabriela Carreno, Jose Mario Gonzalez-Meljem, Scott Haston, Romain Guiho, Julie E Cooper, Saba Manshaei, Nital Jani, Annett Hölsken, Benedetta Pettorini, Robert J Beynon, Deborah M Simpson, Helen C Fraser, Ying Hong, Shirleen Hallang, Thomas J Stone, Alex Virasami, Andrew M Donson, David Jones, Kristian Aquilina, Helen Spoudeas, Abhijit R Joshi, Richard Grundy, Lisa C D Storer, Márta Korbonits, David A Hilton, Kyoko Tossell, Selvam Thavaraj, Mark A Ungless, Jesus Gil, Rolf Buslei, Todd Hankinson, Darren Hargrave, Colin Goding, Cynthia L Andoniadou, Paul Brogan, Thomas S Jacques, Hywel J Williams, Juan Pedro Martinez-Barbera
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset...
March 14, 2018: Acta Neuropathologica
Lotte Kors, Elena Rampanelli, Geurt Stokman, Loes Butter, Ntsiki M Held, Nike Claessen, Per W B Larsen, Joanne Verheij, Coert J Zuurbier, Gerhard Liebisch, Gerd Schmitz, Stephen E Girardin, Sandrine Florquin, Riekelt H Houtkooper, Jaklien C Leemans
NOD-like receptor (NLR)X1 (NLRX1) is an ubiquitously expressed inflammasome-independent NLR that is uniquely localized in mitochondria with as yet unknown effects on metabolic diseases. Here, we report that NLRX1 is essential in regulating cellular metabolism in non-immune parenchymal hepatocytes by decreasing mitochondrial fatty acid-dependent oxidative phosphorylation (OXPHOS) and promoting glycolysis. NLRX1 loss in mice has a profound impact on the prevention of diet-induced metabolic syndrome parameters, non-alcoholic fatty liver disease (NAFLD) progression, and renal dysfunction...
March 4, 2018: Biochimica et Biophysica Acta
Cuong Thach Nguyen, Shyam Kishor Sah, Tae-Yoon Kim
Propionibacterium acnes is a well-known commensal bacterium that plays an important role in the pathogenesis of acne and chronic inflammatory skin disease. In this study, we investigated the effect of superoxide dismutase 3 (SOD3) on P. acnes- or peptidoglycan (PGN)-induced inflammation in vitro and in vivo. Our data demonstrated that SOD3 suppressed toll-like receptor-2 (TLR-2) expression in P. acnes- or PGN-treated keratinocytes and sebocytes. Moreover, we found that SOD3 suppressed the expressions of phosphorylated nuclear factor-κB (NF-κB) and p38 in P...
March 5, 2018: Scientific Reports
Jing Cheng, Fei Xue, Meng Zhang, Cheng Cheng, Lei Qiao, Jing Ma, Wenhai Sui, Xingli Xu, Chengjiang Gao, Panpan Hao, Meng Zhang, Yun Zhang
Tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase of the tripartite motif family, plays an important role in the innate immune response. It can reduce the activity of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, little information is about glucose metabolic health of TRIM31-deficient mice, and investigations about gut microbiota in TRIM31-deficient mice is limited. Thus, we aimed to compare glucose metabolic parameters, gut microbiota composition and inflammatory cytokine levels between TRIM31-/- and wild-type (WT) mice, and further investigate whether or not certain gut microbiota taxon correlates with specific metabolic parameters and inflammation cytokines in TRIM31-deficient mice...
2018: Frontiers in Physiology
Marianne R Spalinger, Roberto Manzini, Larissa Hering, Julianne B Riggs, Claudia Gottier, Silvia Lang, Kirstin Atrott, Antonia Fettelschoss, Florian Olomski, Thomas M Kündig, Michael Fried, Declan F McCole, Gerhard Rogler, Michael Scharl
Variants in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with inflammatory disorders, including inflammatory bowel diseases, rheumatoid arthritis, and type 1 diabetes. The anti-inflammatory role of PTPN2 is highlighted by the fact that PTPN2-deficient mice die a few weeks after birth because of systemic inflammation and severe colitis. However, the tissues, cells, and molecular mechanisms that contribute to this phenotype remain unclear. Here, we demonstrate that myeloid cell-specific deletion of PTPN2 in mice (PTPN2-LysMCre) promotes intestinal inflammation but protects from colitis-associated tumor formation in an IL-1β-dependent manner...
February 13, 2018: Cell Reports
Joyce K Thompson, Anurag Shukla, Alan L Leggett, Phillip B Munson, Jill M Miller, Maximilian B MacPherson, Stacie L Beuschel, Harvey I Pass, Arti Shukla
Malignant mesothelioma is an aggressive cancer in desperate need of treatment. We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice. Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis. First, we show a dose dependent toxicity of XMD8-92 to 2 human mesothelioma cell lines growing as a monolayer...
January 2, 2018: Oncotarget
Di Chen, Brandon J Dixon, Desislava M Doycheva, Bo Li, Yang Zhang, Qin Hu, Yue He, Zongduo Guo, Derek Nowrangi, Jerry Flores, Valery Filippov, John H Zhang, Jiping Tang
BACKGROUND: The endoplasmic reticulum (ER) is responsible for the control of correct protein folding and protein function which is crucial for cell survival. However, under pathological conditions, such as hypoxia-ischemia (HI), there is an accumulation of unfolded proteins thereby triggering the unfolded protein response (UPR) and causing ER stress which is associated with activation of several stress sensor signaling pathways, one of them being the inositol requiring enzyme-1 alpha (IRE1α) signaling pathway...
February 2, 2018: Journal of Neuroinflammation
Marine Groslambert, Bénédicte F Py
The innate immunity constitutes an efficient barrier by rapidly detecting pathogens and tissue damages through pattern recognition receptors including NLRP3. Moreover, inappropriate NLRP3 activation causes deleterious inflammation and contributes to various conditions including atherosclerosis, diabetes, gout and Alzheimer's diseases. NLRP3 assembles a multimeric inflammasome complex serving as an activation platform for caspase-1 that controls processing and release of cytosolic inflammatory factors and cytokines including IL-1β Inflammasome assembly is tightly controlled and requires coordinated NLRP3 priming, through cytokine or other pattern recognition receptors, followed by activation by cellular stress...
January 2018: Médecine Sciences: M/S
Carlo Marchetti, Benjamin Swartzwelter, Fabia Gamboni, Charles P Neff, Katrin Richter, Tania Azam, Sonia Carta, Isak Tengesdal, Travis Nemkov, Angelo D'Alessandro, Curtis Henry, Gerald S Jones, Scott A Goodrich, Joseph P St Laurent, Terry M Jones, Curtis L Scribner, Robert B Barrow, Roy D Altman, Damaris B Skouras, Marco Gattorno, Veronika Grau, Sabina Janciauskiene, Anna Rubartelli, Leo A B Joosten, Charles A Dinarello
Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Xia Li, Yu Zhang, Quan Jin, Kai-Li Xia, Min Jiang, Ben-Wen Cui, Yan-Ling Wu, Shun-Zong Song, Li-Hua Lian, Ji-Xing Nan
BACKGROUND AND PURPOSE: Regulating P2x7R-NLRP3 inflammasome activation might be a potential therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process would be modulated by gentiopicroside (GPS), which is the main active secoiridoid glycoside from Gentiana manshurica Kitagawa. EXPERIMENTAL APPROACH: In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administrated ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice...
January 16, 2018: British Journal of Pharmacology
Yicong Wei, Jianxiong Chen, Yonghong Hu, Wei Lu, Xiaoqin Zhang, Ruiguo Wang, Kedan Chu
The excessive activation of microglia plays a key role in the pathogenesis of neurodegenerative diseases. The neuroprotective properties of rosmarinic acid have been reported in a variety of disease models both in vitro and in vivo; however, the mechanism underlying its anti-neuroinflammatory activity has not been clearly elucidated. In the present study, we evaluated the anti-inflammatory effects of rosmarinic acid in conditions of neuroinflammatory injury in vitro and in vivo. The results indicated that rosmarinic acid reduced the expression of CD11b, a marker of microglia and macrophages, in the brain and dramatically inhibited the levels of inflammatory cytokines and mediators, such as TNFα, IL-6, IL-1β, COX-2, and iNOS, in a dose-dependent manner both in vitro and in vivo...
January 9, 2018: Inflammation
Cira Dansokho, Michael Thomas Heneka
Neuroinflammatory responses in Alzheimer's disease (AD) are complex and not fully understood. They involve various cellular and molecular players and associate interaction between the central nervous system (CNS) and the periphery. Amyloid peptides within the senile plaques and abnormally phosphorylated tau in neurofibrillary tangles are able to initiate inflammatory responses, in brain of AD patients and in mouse models of this disease. The outcome of these responses on the pathophysiology of AD depends on several factors and can be either beneficial or detrimental...
December 22, 2017: Journal of Neural Transmission
Keren Zhou, Budbazar Enkhjargal, Zhiyi Xie, Chengmei Sun, Lingyun Wu, Jay Malaguit, Sheng Chen, Jiping Tang, Jianmin Zhang, John H Zhang
BACKGROUND AND PURPOSE: The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. METHODS: SAH was induced by endovascular perforation in male Sprague-Dawley rats...
January 2018: Stroke; a Journal of Cerebral Circulation
Yue-Lu Zhang, Ruo-Bing Wang, Wei-Yi Li, Fang-Zhou Xia, Lin Liu
AIM: To explore the role of Pioglitazone (Pio) on a mouse model of retinal ischemia/reperfusion (I/R) injury and to elucidate the potential mechanism. METHODS: Retinal ischemia was induced in mice by increasing the intraocular pressure, and Pio was administered 4h though periocular injection before I/R. The number of cells in the ganglion cell layer (GCL) was counted 7d after retinal I/R injury. Glial fibrillary acidic protein (GFAP), nuclear factor-kappa B (NF-κB), p38, phosphorylated-p38, PPAR-γ, interleukin-1β (IL-1β), Toll-like receptor 4 (TLR4), NLRP3, cleaved caspase-1, caspase-1 were determined by real-time polymerase chain reaction and Western blotting...
2017: International Journal of Ophthalmology
Kristen T Crowell, Samantha Moreno, Jennifer L Steiner, Catherine S Coleman, David I Soybel, Charles H Lang
BACKGROUND: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose of this study was to investigate diverse signal transduction pathways that regulate myocardial protein synthesis and degradation. METHODS: Adult male C57BL/6 mice were used to identify potential mechanisms mediating the acute (24 h) effect of cecal ligation and puncture (CLP) as well as long-term changes that manifest during the chronic (10 d) recovery phase...
December 13, 2017: Shock
Maosheng Xia, Xiaowei Li, Li Yang, Jiaan Ren, Guangfeng Sun, Shuang Qi, Alexei Verkhratsky, Baoman Li
It is well known that sleep disorders are harmful to people's health and performance, and growing evidence suggests that sleep deprivation (SD) can trigger neuroinflammation in the brain. The nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome is reported to be relevant to the neuroinflammation induced by SD, but the regulatory signaling that governs the NLRP3 inflammasome in SD is still unknown. Meanwhile, whether the regulatory action of antidepressants in astrocytes could affect the neuroinflammation induced by SD also remains obscure...
December 9, 2017: Journal of Neurochemistry
Deepika Sharma, Ankit Malik, Clifford S Guy, Rajendra Karki, Peter Vogel, Thirumala-Devi Kanneganti
BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with IBD. We investigated the role of pyrin in intestinal homeostasis in mice. METHODS: Mefv-/- mice and C57/BL6 mice (controls) were given azoxymethane followed by multiple rounds of dextran sodium sulfate (DSS) to induce colitis and tumorigenesis...
December 2, 2017: Gastroenterology
Jie Qu, Xue-You Tao, Peng Teng, Yan Zhang, Ci-Liang Guo, Liang Hu, Yan-Ning Qian, Chun-Yi Jiang, Wen-Tao Liu
BACKGROUND: Long-term use of morphine induces analgesic tolerance, which limits its clinical efficacy. Evidence indicated morphine-evoked neuroinflammation mediated by toll-like receptor 4 (TLR4) - NOD-like receptor protein 3 (NLRP3) inflammasome was important for morphine tolerance. In our study, we investigated whether other existing alternative pathways caused morphine-induced activation of TLR4 in microglia. We focused on heat shock protein 70 (HSP70), a damage-associated molecular pattern (DAMP), which was released from various cells upon stimulations under the control of KATP channel and bound with TLR4-inducing inflammation...
November 25, 2017: Journal of Neuroinflammation
Stephanie Dabo, Patrick Maillard, Milagros Collados Rodriguez, Marianne Doré Hansen, Sabrina Mazouz, Donna-Joe Bigot, Marion Tible, Geneviève Janvier, Olivier Helynck, Patricia Cassonnet, Yves Jacob, Jacques Bellalou, Anne Gatignol, Rekha C Patel, Jacques Hugon, Hélène Munier-Lehmann, Eliane F Meurs
PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy...
November 23, 2017: Scientific Reports
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