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Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome.
Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R, Li S, Fowler BJ, Bastos-Carvalho A, Kerur N, Uittenbogaard A, Han YS, Lou D, Kleinman ME, McDonald WH, Núñez G, Georgel P, Dunaief JL, Ambati J
(2015) Cell Rep 11: 1686-93
MeSH Terms: Alu Elements, Animals, Carrier Proteins, Caspase 1, DEAD-box RNA Helicases, Inflammasomes, Iron, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, RNA-Binding Proteins, Retinal Pigment Epithelium, Ribonuclease III
Show Abstract · Added January 26, 2016
Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection.
Callaway JB, Smith SA, McKinnon KP, de Silva AM, Crowe JE, Ting JP
(2015) J Biol Chem 290: 17306-20
MeSH Terms: Antibodies, Viral, Antibody-Dependent Enhancement, Antigen-Antibody Complex, Carrier Proteins, Caspase 1, Cells, Cultured, Dengue, Dengue Virus, Glyburide, Humans, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Monocytes, NLR Family, Pyrin Domain-Containing 3 Protein, Protein-Tyrosine Kinases, RNA, Messenger, RNA, Small Interfering, Syk Kinase, Virus Replication
Show Abstract · Added January 26, 2016
Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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20 MeSH Terms
Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection.
Nagamatsu K, Hannan TJ, Guest RL, Kostakioti M, Hadjifrangiskou M, Binkley J, Dodson K, Raivio TL, Hultgren SJ
(2015) Proc Natl Acad Sci U S A 112: E871-80
MeSH Terms: Acute Disease, Animals, Apoptosis, Bacterial Proteins, Carrier Proteins, Caspase 1, Chronic Disease, Colony Count, Microbial, Disease Progression, Enzyme Activation, Escherichia coli Infections, Escherichia coli Proteins, Female, Gene Expression Regulation, Bacterial, Hemolysin Proteins, Humans, Inflammasomes, Interleukin-1beta, Mice, Models, Biological, NLR Family, Pyrin Domain-Containing 3 Protein, Signal Transduction, Urinary Bladder, Urinary Tract Infections, Uropathogenic Escherichia coli, Virulence
Show Abstract · Added February 16, 2016
Urinary tract infections (UTIs) are among the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. Uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs, invades bladder epithelial cells (BECs) and develops into clonal intracellular bacterial communities (IBCs). Upon maturation, IBCs disperse, with bacteria spreading to neighboring BECs to repeat this cycle. This process allows UPEC to gain a foothold in the face of innate defense mechanisms, including micturition, epithelial exfoliation, and the influx of polymorphonuclear leukocytes. Here, we investigated the mechanism and dynamics of urothelial exfoliation in the early acute stages of infection. We show that UPEC α-hemolysin (HlyA) induces Caspase-1/Caspase-4-dependent inflammatory cell death in human urothelial cells, and we demonstrate that the response regulator (CpxR)-sensor kinase (CpxA) two-component system (CpxRA), which regulates virulence gene expression in response to environmental signals, is critical for fine-tuning HlyA cytotoxicity. Deletion of the cpxR transcriptional response regulator derepresses hlyA expression, leading to enhanced Caspase-1/Caspase-4- and NOD-like receptor family, pyrin domain containing 3-dependent inflammatory cell death in human urothelial cells. In vivo, overexpression of HlyA during acute bladder infection induces more rapid and extensive exfoliation and reduced bladder bacterial burdens. Bladder fitness is restored fully by inhibition of Caspase-1 and Caspase-11, the murine homolog of Caspase-4. Thus, we have discovered that fine-tuning of HlyA expression by the CpxRA system is critical for enhancing UPEC fitness in the urinary bladder. These results have significant implications for our understanding of how UPEC establishes persistent colonization.
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26 MeSH Terms
Preconditioning mesenchymal stem cells with caspase inhibition and hyperoxia prior to hypoxia exposure increases cell proliferation.
Saini U, Gumina RJ, Wolfe B, Kuppusamy ML, Kuppusamy P, Boudoulas KD
(2013) J Cell Biochem 114: 2612-23
MeSH Terms: Amino Acid Chloromethyl Ketones, Animals, Caspase 1, Caspase 3, Caspase 6, Caspase 7, Caspase 9, Cell Hypoxia, Cell Proliferation, Cells, Cultured, Male, Mesenchymal Stem Cells, Rats
Show Abstract · Added February 21, 2015
Myocardial infarction is a leading cause of mortality and morbidity worldwide. Occlusion of a coronary artery produces ischemia and myocardial necrosis that leads to left ventricular (LV) remodeling, dysfunction, and heart failure. Stem cell therapy may decrease infarct size and improve LV function; the hypoxic environment, however, following a myocardial infarction may result in apoptosis, which in turn decreases survival of transplanted stem cells. Therefore, the effects of preconditioned mesenchymal stem cells (MSC) with hyperoxia (100% oxygen), Z-VAD-FMK pan-caspase inhibitor (CI), or both in a hypoxic environment in order to mimic conditions seen in cardiac tissue post-myocardial infarction were studied in vitro. MSCs preconditioned with hyperoxia or CI significantly decreased apoptosis as suggested by TUNEL assay and Annexin V analysis using fluorescence assisted cell sorting. These effects were more profound when both, hyperoxia and CI, were used. Additionally, gene and protein expression of caspases 1, 3, 6, 7, and 9 were down-regulated significantly in MSCs preconditioned with hyperoxia, CI, or both, while the survival markers Akt1, NF-κB, and Bcl-2 were significantly increased in preconditioned MSCs. These changes ultimately resulted in a significant increase in MSC proliferation in hypoxic environment as determined by BrdU assays compared to MSCs without preconditioning. These effects may prove to be of great clinical significance when transplanting stem cells into the hypoxic myocardium of post-myocardial infarction patients in order to attenuate LV remodeling and improve LV function.
© 2013 Wiley Periodicals, Inc.
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13 MeSH Terms
Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.
Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, Brittnacher MJ, Fong C, Radey M, Ogohara C, Stark AL, Akey JM, Dolan ME, Wurfel MM, Miller SI
(2012) Proc Natl Acad Sci U S A 109: E2343-52
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Apoptosis, Apoptosis Regulatory Proteins, Bone Marrow Cells, Caspase 1, Caspase 9, Deoxyadenosines, Genetic Predisposition to Disease, Genetic Variation, HEK293 Cells, HapMap Project, Humans, Methionine, Mice, Mice, Inbred C57BL, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Salmonella Infections, Salmonella typhimurium, Thionucleosides, Young Adult
Show Abstract · Added April 13, 2017
Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5'-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5'-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.
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25 MeSH Terms
Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis.
Ippagunta SK, Brand DD, Luo J, Boyd KL, Calabrese C, Stienstra R, Van de Veerdonk FL, Netea MG, Joosten LA, Lamkanfi M, Kanneganti TD
(2010) J Biol Chem 285: 12454-62
MeSH Terms: Animals, Apoptosis Regulatory Proteins, Arthritis, Experimental, Autoantibodies, CARD Signaling Adaptor Proteins, Carrier Proteins, Caspase 1, Collagen, Cytoskeletal Proteins, Dendritic Cells, Humans, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein, T-Lymphocytes
Show Abstract · Added March 20, 2014
Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis.
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17 MeSH Terms
The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.
Thomas PG, Dash P, Aldridge JR, Ellebedy AH, Reynolds C, Funk AJ, Martin WJ, Lamkanfi M, Webby RJ, Boyd KL, Doherty PC, Kanneganti TD
(2009) Immunity 30: 566-75
MeSH Terms: Animals, Antigen-Presenting Cells, Carrier Proteins, Caspase 1, Cells, Cultured, Gene Expression Regulation, Genetic Predisposition to Disease, Immunity, Innate, Influenza A virus, Interleukin-1beta, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein
Show Abstract · Added March 5, 2014
Virus-induced interlukin-1beta (IL-1beta) and IL-18 production in macrophages are mediated via caspase-1 pathway. Multiple microbial components, including viral RNA, are thought to trigger assembly of the cryopyrin inflammasome resulting in caspase-1 activation. Here, we demonstrated that Nlrp3(-/-) and Casp1(-/-) mice were more susceptible than wild-type mice after infection with a pathogenic influenza A virus. This enhanced morbidity correlated with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production. Despite the effect on innate immunity, cryopyrin-deficiency was not associated with any obvious defect in virus control or on the later emergence of the adaptive response. Early epithelial necrosis was, however, more severe in the infected mutants, with extensive collagen deposition leading to later respiratory compromise. These findings reveal a function of the cryopyrin inflammasome in healing responses. Thus, cryopyrin and caspase-1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.
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14 MeSH Terms
Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival.
Lamkanfi M, Moreira LO, Makena P, Spierings DC, Boyd K, Murray PJ, Green DR, Kanneganti TD
(2009) Blood 113: 2742-5
MeSH Terms: Animals, Apoptosis, Caspase 1, Caspase 3, Caspase 7, Chemokines, Cytokines, Endotoxemia, Endotoxins, Enzyme Activation, Injections, Intraperitoneal, Lymphocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Specific Pathogen-Free Organisms, Spleen
Show Abstract · Added March 5, 2014
Extensive apoptosis of leukocytes during sepsis and endotoxic shock constitutes an important mechanism linked to the excessive mortality associated with these disorders. Caspase inhibitors confer protection from endotoxin-induced lymphocyte apoptosis and improve survival, but it is not clear which caspases mediate lipopolysaccharide (LPS)-induced lymphocyte apoptosis and mortality. We report here that the apoptotic executioner caspase-7 was activated in the splenocytes of LPS-injected mice, suggesting a role for caspase-7 in lymphocyte apoptosis. Indeed, caspase-7-deficient mice were resistant to LPS-induced lymphocyte apoptosis and were markedly protected from LPS-induced lethality independently of the excessive production of serum cytokines. These results reveal for the first time a nonredundant role for caspase-7 in vivo and identify caspase-7 inhibition as a component of the mechanism by which caspase inhibitors protect from endotoxin-induced mortality.
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17 MeSH Terms
Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells.
Shimada M, Ando T, Peek RM, Watanabe O, Ishiguro K, Maeda O, Ishikawa D, Hasegawa M, Ina K, Ohmiya N, Niwa Y, Goto H
(2008) Eur J Gastroenterol Hepatol 20: 1144-50
MeSH Terms: Adult, Aged, Apoptosis, Caspase 1, Caspase 3, Cells, Cultured, Dyspepsia, Epithelial Cells, Fas Ligand Protein, Female, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Interferon-gamma, Interleukin-18, Male, Middle Aged, Organ Culture Techniques, Stomach Ulcer, Up-Regulation
Show Abstract · Added March 5, 2014
BACKGROUND - Helicobacter pylori infection induces a biased T helper type 1 (Th1) response that produces IFN-gamma and Fas ligand (FasL). Th1 cytokines are associated with apoptosis in the gastric epithelial cells.
AIM - We aimed to define the role of the recently cloned IL-18, a IFN-gamma inducing factor, in gastric mucosal injury induced by H. pylori infection.
METHODS - Twenty-seven gastric ulcer (GU) patients and 20 functional dyspepsia (FD) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used for histological examination, H. pylori culture and in-situ stimulation for 48 h in the presence of 10 microg/ml phytohemagglutinin-P. IL-18, IFN-gamma, and soluble FasL (sFasL) levels in culture supernatants were assayed by the enzyme-linked immunosorbent assay method. IL-18, IL-1beta-converting enzyme (ICE) and caspase-3 were evaluated by western blotting in gastric cancer cell lines (MKN45) cocultured with H. pylori.
RESULTS - All 27 GU patients and ten out of 20 FD patients were found to be H. pylori-positive, whereas ten FD patients were H. pylori-negative. Antral mucosal tissues from H. pylori-positive FD patients contained (P<0.01) higher levels of IL-18, IFN-gamma, and sFasL than those from uninfected FD patients. IL-18, IFN-gamma, and sFasL levels at the ulcer site were significantly (P<0.01) higher than those at distant sites in the antrum. A significant relationship was seen between IL-18 and IFN-gamma levels at the ulcer site (r=0.7, P<0.01). H. pylori eradication led to a significant decrease in the levels of IL-18, IFN-gamma, and sFasL at the ulcer site. Western blotting showed that IL-18, ICE, and caspase-3 were activated in gastric cancer cell lines cocultured with H. pylori.
CONCLUSION - This study suggests that H. pylori infection enhanced mucosal injury by stimulating a Th1 response, which was mediated by IL-18 upregulation as well as activation of ICE and caspase-3.
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21 MeSH Terms
Versatile prostate cancer treatment with inducible caspase and interleukin-12.
Nikitina EY, Desai SA, Zhao X, Song W, Luo AZ, Gangula RD, Slawin KM, Spencer DM
(2005) Cancer Res 65: 4309-19
MeSH Terms: Adenocarcinoma, Adenoviridae, Animals, Apoptosis, B7-1 Antigen, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cancer Vaccines, Caspase 1, Dendritic Cells, Interferon-gamma, Interleukin-12, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Prostatic Neoplasms, T-Lymphocytes, Cytotoxic
Show Abstract · Added April 7, 2010
To establish optimized conditions for immunity against prostate cancer, we compared the efficacy of multiple approaches in autochthonous and s.c. transgenic adenocarcinoma of the mouse prostate (TRAMP)-based models. Mice immunized with interleukin (IL)-12-containing apoptotic, but not necrotic TRAMP-C2 cell-based, vaccines were resistant to TRAMP-C2 tumor challenge and re-challenge, independently of the route of vaccination (s.c. or i.p.). Administration of gamma-irradiated TRAMP-C2 cells preinfected with adenovirus containing both B7-1 and IL-12 genes, unlike adenovirus containing B7-1 alone, considerably protected C57BL/6 mice from TRAMP-C2 tumor growth and extended the life span of TRAMP mice. Vaccines that included dendritic cells, instead of IL-12, were equally efficient. Whereas injections of ligand-inducible caspase-1- and IL-12-containing adenoviruses cured small s.c. TRAMP-C2 tumors, nanopump-regulated delivery of viruses led to elimination of much larger tumors. The antitumor immune responses involved CD4+-, CD8+-, and natural killer cells and were strengthened by increasing the number of vaccinations. Intraprostatic administration of inducible caspase-1- and IL-12-containing adenoviruses resulted in local cell death and improved survival of adenocarcinoma-bearing TRAMP mice. Thus, tumor cell apoptosis induced by caspase in situ and accompanied by IL-12 is efficient against prostate cancer in a preclinical model.
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18 MeSH Terms