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Bamboo Vinegar Decreases Inflammatory Mediator Expression and NLRP3 Inflammasome Activation by Inhibiting Reactive Oxygen Species Generation and Protein Kinase C-α/δ Activation  [PDF]
Chen-Lung Ho, Chai-Yi Lin, Shuk-Man Ka, Ann Chen, Yu-Ling Tasi, May-Lan Liu, Yi-Chich Chiu, Kuo-Feng Hua
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075738
Abstract: Bamboo vinegar (BV), a natural liquid derived from the condensation produced during bamboo charcoal production, has been used in agriculture and as a food additive, but its application to immune modulation has not been reported. Here, we demonstrated that BV has anti-inflammatory activities both in vitro and in vivo. BV reduced inducible nitric oxide synthase expression and nitric oxide levels in, and interleukin-6 secretion by, lipopolysaccharide-activated macrophages without affecting tumor necrosis factor-α secretion and cyclooxygenase-2 expression. The mechanism for the anti-inflammatory effect of BV involved decreased reactive oxygen species production and protein kinase C-α/δ activation. Furthermore, creosol (2-methoxy-4-methylphenol) was indentified as the major anti-inflammatory compound in BV. Impaired cytokine expression and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation was seen in mice treated with creosol. These findings provide insights into how BV regulates inflammation and suggest that it may be a new source for the development of anti-inflammatory agents or a healthy supplement for preventing and ameliorating inflammation- and NLRP3 inflammasome-related diseases, including metabolic syndrome.
Polyenylpyrrole Derivatives Inhibit NLRP3 Inflammasome Activation and Inflammatory Mediator Expression by Reducing Reactive Oxygen Species Production and Mitogen-Activated Protein Kinase Activation  [PDF]
Kuo-Feng Hua, Ju-Ching Chou, Yulin Lam, Yu-Ling Tasi, Ann Chen, Shuk-Man Ka, Zhanxiong Fang, May-Lan Liu, Feng-Ling Yang, Yu-Liang Yang, Yi-Chich Chiu, Shih-Hsiung Wu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076754
Abstract: Two polyenylpyrroles from a soil ascomycete Gymnoascus reessii were previously identified as hit compounds in screening for cytotoxicity against lung cancer cells. These compounds and various analogs, which have been previously synthesized and tested for anti-lung cancer cell activity, were tested for anti-inflammatory activity. After preliminary screening for cytotoxicity for RAW 264.7 murine macrophage cells, the non-toxic compounds were tested for anti-inflammatory activity using lipopolysaccharide (LPS)-activated RAW 264.7 cells. Compounds 1h, 1i, and 1n reduced LPS-induced nitric oxide (NO) production, with respective ED50 values of 15 ± 2, 16 ± 2, and 17 ± 2 μM. They also reduced expression of inducible NO synthase and interleukin-6 (IL-6) without affecting cyclooxygenase-2 expression. Compound 1h also reduced secretion of IL-6 and tumor necrosis factor-α by LPS-activated J774A.1 murine macrophage cells, primary mice peritoneal macrophages, and JAWSII murine bone marrow-derived dendritic cells and reduced NLRP3 inflammasome-mediated interleukin-1β (IL-1β) secretion by LPS + adenosine triphosphate-activated J774A.1 and JAWSII cells. The underlying mechanisms for the anti-inflammatory activity of compound 1h were found to be a decrease in LPS-induced reactive oxygen species (ROS) production, mitogen-activated protein kinase phosphorylation, and NF-κB activation and a decrease in ATP-induced ROS production and PKC-α phosphorylation. These results provide promising insights into the anti-inflammatory activity of these conjugated polyenes and a molecular rationale for future therapeutic intervention in inflammation-related diseases. They also show how compound 1h regulates inflammation and suggest it may be a new source for the development of anti-inflammatory agents to ameliorate inflammation- and NLRP3 inflammasome-related diseases.
NLRP3 Inflammasome and MS/EAE  [PDF]
Makoto Inoue,Mari L. Shinohara
Autoimmune Diseases , 2013, DOI: 10.1155/2013/859145
Abstract: Inflammasomes are cytosolic sensors that detect pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is known to detect a wide array of microbes and endogenous damage-associated molecules. Possible involvement of the NLRP3 inflammasome (or inflammasomes) in the development of multiple sclerosis (MS) was suggested in a number of studies. Recent studies showed that the NLRP3 inflammasome exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS, although EAE can also develop without the NLRP3 inflammasome. In this paper, we discuss the NLRP3 inflammasome in MS and EAE development. 1. Inflammasomes Inflammasomes are cytosolic sensors that detect pathogens and stresses in order to mature and secrete proinflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. Inflammasomes are expressed in phagocytes, such as macrophages and dendritic cells (DCs), and form a multiprotein complex that activates caspase-1. Assembly of inflammasomes that have clear physiological functions in vivo has been reported with relatively few NOD-like receptor (NLR) family members, such as NLRP1, NLRP3 (also called cryopyrin, CIAS1, NALP3), NLRC4 (IRAF), and AIM2 [1]. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is comprised of three different proteins: NLRP3, adapter protein apoptosis-associated speck-like protein (ASC), and procaspase-1. NLRP3 protein is autorepressed by an internal interaction between the NACHT domain and leucine-rich repeats (LRRs) (Figure 1(a)) [2, 3]. Derepression of NLRP3 is essential for the interaction between NLRP3 and ASC through their Pyrin domains (PYD), followed by further interaction between ASC and procaspase-1 through CARD domains (caspase activation and recruitment domains) (Figure 1(b)). Oligomerization of the NLRP3 inflammasome heterotrimer unit leads to procaspase-1 self-cleavage to generate activated caspase-1, which processes maturation of IL-1β and IL-18 and elicits rapid release of those inflammatory cytokines by cell death termed “pyroptosis” (Figure 1(c)). Molecular mechanism by which caspase-1 mediates pyroptosis is still elusive, but is distinguished from apoptosis and necrosis [4, 5]. A molecule termed CARDINAL is known to be involved in the human NLRP3 inflammasome [6] (Figure 1(b)); but its function is unknown and there is no mouse homolog of human CARDINAL. Critical role of CARDINAL in eliciting functions of inflammasomes is questioned, because mouse inflammasomes share basic
NLRP3 Inflammasome Activation by Paracoccidioides brasiliensis  [PDF]
Aldo Henrique Tavares equal contributor ,Kelly Grace Magalh?es equal contributor,Raquel Das Neves Almeida,Rafael Correa,Pedro Henrique Burgel,Anamélia Lorenzetti Bocca
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002595
Abstract: Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis that is geographically confined to Latin America. The pro-inflammatory cytokine IL-1β that is mainly derived from the activation of the cytoplasmic multiprotein complex inflammasome is an essential host factor against opportunistic fungal infections; however, its role in infection with a primary fungal pathogen, such as P. brasiliensis, is not well understood. In this study, we found that murine bone marrow-derived dendritic cells responded to P. brasiliensis yeast cells infection by releasing IL-1β in a spleen tyrosine kinase (Syk), caspase-1 and NOD-like receptor (NLR) family member NLRP3 dependent manner. In addition, P. brasiliensis-induced NLRP3 inflammasome activation was dependent on potassium (K+) efflux, reactive oxygen species production, phagolysosomal acidification and cathepsin B release. Finally, using mice lacking the IL-1 receptor, we demonstrated that IL-1β signaling has an important role in killing P. brasiliensis by murine macrophages. Altogether, our results demonstrate that the NLRP3 inflammasome senses and responds to P. brasiliensis yeast cells infection and plays an important role in host defense against this fungus.
The role of the NLRP3 inflammasome in gout
Sarah R Kingsbury, Philip G Conaghan, Michael F McDermott
Journal of Inflammation Research , 2011, DOI: http://dx.doi.org/10.2147/JIR.S11330
Abstract: ole of the NLRP3 inflammasome in gout Review (5605) Total Article Views Authors: Sarah R Kingsbury, Philip G Conaghan, Michael F McDermott Published Date March 2011 Volume 2011:4 Pages 39 - 49 DOI: http://dx.doi.org/10.2147/JIR.S11330 Sarah R Kingsbury1,2, Philip G Conaghan1,2, Michael F McDermott1,2 1Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine 2NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK Abstract: Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Recent studies suggest that orchestration of the MSU-induced inflammatory response is dependent on the proinflammatory cytokine IL-1 , underlined by promising results in early IL-1 inhibitor trials in gout patients. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in response to the MSU 'danger signal'. This review focuses on our current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks. It also discusses the management of treatment-resistant acute and chronic tophaceous gout with IL-1 inhibitors; early clinical studies of rilonacept (IL-1 Trap), canakinumab (monoclonal anti-IL-1 antibody), and anakinra have all demonstrated treatment efficacy in such patients.
The role of the NLRP3 inflammasome in gout
Sarah R Kingsbury,Philip G Conaghan,Michael F McDermott
Journal of Inflammation Research , 2011,
Abstract: Sarah R Kingsbury1,2, Philip G Conaghan1,2, Michael F McDermott1,21Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine 2NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UKAbstract: Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Recent studies suggest that orchestration of the MSU-induced inflammatory response is dependent on the proinflammatory cytokine IL-1 , underlined by promising results in early IL-1 inhibitor trials in gout patients. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in response to the MSU 'danger signal'. This review focuses on our current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks. It also discusses the management of treatment-resistant acute and chronic tophaceous gout with IL-1 inhibitors; early clinical studies of rilonacept (IL-1 Trap), canakinumab (monoclonal anti-IL-1 antibody), and anakinra have all demonstrated treatment efficacy in such patients.Keywords: gout, inflammasome, NLRP3, IL-1
NLRP3 Inflammasome and Pathobiology in AMD  [PDF]
Lucia Celkova,Sarah L. Doyle,Matthew Campbell
Journal of Clinical Medicine , 2015, DOI: 10.3390/jcm4010172
Abstract: Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by drusen deposition between the RPE and underlying choroid and accumulation of lipofuscin in the RPE. End-stage disease is characterized by geographic atrophy (dry AMD) or choroidal neovascularization (wet AMD). The NLRP3 inflammasome has recently been implicated in the disease pathology. Here we review the current knowledge on the involvement of this multiprotein complex and its effector cytokines interleukin-1β (IL-1β) and IL-18 in AMD progression. We also describe cell death mechanisms that have been proposed to underlie RPE degeneration in AMD and discuss the role of autophagy in the regulation of disease progression.
Rac1 Regulates the NLRP3 Inflammasome Which Mediates IL-1beta Production in Chlamydophila pneumoniae Infected Human Mononuclear Cells  [PDF]
Julia Eitel, Karolin Meixenberger, Claudia van Laak, Christine Orlovski, Andreas Hocke, Bernd Schmeck, Stefan Hippenstiel, Philippe Dje N'Guessan, Norbert Suttorp, Bastian Opitz
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030379
Abstract: Chlamydophila pneumoniae causes acute respiratory tract infections and has been associated with development of asthma and atherosclerosis. The production of IL-1β, a key mediator of acute and chronic inflammation, is regulated on a transcriptional level and additionally on a posttranslational level by inflammasomes. In the present study we show that C. pneumoniae-infected human mononuclear cells produce IL-1β protein depending on an inflammasome consisting of NLRP3, the adapter protein ASC and caspase-1. We further found that the small GTPase Rac1 is activated in C. pneumoniae-infected cells. Importantly, studies with specific inhibitors as well as siRNA show that Rac1 regulates inflammasome activation in C. pneumoniae-infected cells. In conclusion, C. pneumoniae infection of mononuclear cells stimulates IL-1β production dependent on a NLRP3 inflammasome-mediated processing of proIL-1β which is controlled by Rac1.
Activation of an NLRP3 Inflammasome Restricts Mycobacterium kansasii Infection  [PDF]
Chang-Chieh Chen, Sheng-Hui Tsai, Chia-Chen Lu, Shiau-Ting Hu, Ting-Shu Wu, Tsung-Teng Huang, Najwane Sa?d-Sadier, David M. Ojcius, Hsin-Chih Lai
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036292
Abstract: Mycobacterium kansasii has emerged as an important nontuberculous mycobacterium pathogen, whose incidence and prevalence have been increasing in the last decade. M. kansasii can cause pulmonary tuberculosis clinically and radiographically indistinguishable from that caused by Mycobacterium tuberculosis infection. Unlike the widely-studied M. tuberculosis, little is known about the innate immune response against M. kansasii infection. Although inflammasome activation plays an important role in host defense against bacterial infection, its role against atypical mycobacteria remains poorly understood. In this report, the role of inflammasome activity in THP-1 macrophages against M. kansasii infection was studied. Results indicated that viable, but not heat-killed, M. kansasii induced caspase-1-dependent IL-1β secretion in macrophages. The underlying mechanism was found to be through activation of an inflammasome containing the NLR (Nod-like receptor) family member NLRP3 and the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). Further, potassium efflux, lysosomal acidification, ROS production and cathepsin B release played a role in M. kansasii-induced inflammasome activation. Finally, the secreted IL-1β derived from caspase-1 activation was shown to restrict intracellular M. kansasii. These findings demonstrate a biological role for the NLRP3 inflammasome in host defense against M. kansasii.
Staphylococcus aureus Activates the NLRP3 Inflammasome in Human and Rat Conjunctival Goblet Cells  [PDF]
Victoria E. McGilligan, Meredith S. Gregory-Ksander, Dayu Li, Jonathan E. Moore, Robin R. Hodges, Michael S. Gilmore, Tara C. B. Moore, Darlene A. Dartt
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074010
Abstract: The conjunctiva is a moist mucosal membrane that is constantly exposed to an array of potential pathogens and triggers of inflammation. The NACHT, leucine rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) is a Nod-like receptor that can sense pathogens or other triggers, and is highly expressed in wet mucosal membranes. NLRP3 is a member of the multi-protein complex termed the NLRP3 inflammasome that activates the caspase 1 pathway, inducing the secretion of biologically active IL-1β, a major initiator and promoter of inflammation. The purpose of this study was to: (1) determine whether NLRP3 is expressed in the conjunctiva and (2) determine whether goblet cells specifically contribute to innate mediated inflammation via secretion of IL-1β. We report that the receptors known to be involved in the priming and activation of the NLRP3 inflammasome, the purinergic receptors P2X4 and P2X7 and the bacterial Toll-like receptor 2 are present and functional in conjunctival goblet cells. Toxin-containing Staphylococcus aureus (S. aureus), which activates the NLRP3 inflammasome, increased the expression of the inflammasome proteins NLRP3, ASC and pro- and mature caspase 1 in conjunctival goblet cells. The biologically active form of IL-1β was detected in goblet cell culture supernatants in response to S. aureus, which was reduced when the cells were treated with the caspase 1 inhibitor Z-YVAD. We conclude that the NLRP3 inflammasome components are present in conjunctival goblet cells. The NRLP3 inflammasome appears to be activated in conjunctival goblet cells by toxin-containing S. aureus via the caspase 1 pathway to secrete mature IL1-β. Thus goblet cells contribute to the innate immune response in the conjunctiva by activation of the NLRP3 inflammasome.
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