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Jing Qiu, Min Wang, Jun Zhang, Qing Cai, Dan Lu, Yansong Li, Yushu Dong, Tianzhi Zhao, Huisheng Chen
Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro...
October 18, 2016: International Immunopharmacology
Olivier Huet, Raelene J Pickering, Chris Tikellis, Celine Latouche, Fenella Long, Bronwyn Kingwell, Bryan Dickinson, Chris J Chang, Seth Masters, Fabienne Mackay, Mark E Cooper, Judy B de Haan
OBJECTIVES: To study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. SETTING: Laboratory experiments. SUBJECTS: C57Bl6 and glutathione peroxidase 1 knockout mice. INTERVENTION: Murine acute pneumonia model induced by Klebsiella pneumonia. MEASUREMENTS AND MAIN RESULTS: We show here that despite a lack of one of the major antioxidant defense enzymes, glutathione peroxidase 1 knockout mice are protected during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice...
October 3, 2016: Critical Care Medicine
Angèle Nalbandian, Arif A Khan, Ruchi Srivastava, Katrina J Llewellyn, Baichang Tan, Nora Shukr, Yasmin Fazli, Virginia E Kimonis, Lbachir BenMohamed
Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP(R155H/+) heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β((+))F4/80((+))Ly6C((+)) inflammatory macrophages that infiltrate the muscles of VCP(R155H/+) mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β((+))F4/80((+))Ly6C((+)) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP(R155H/+) mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80((+))Ly6C((+))IL-1β((+)) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength...
October 11, 2016: Inflammation
Thomas A Kufer, Giulia Nigro, Philippe J Sansonetti
NOD-like receptor (NLR) proteins, as much as Toll-like receptor proteins, play a major role in modulating myeloid cells in their immune functions. There is still, however, limited knowledge on the expression and function of several of the mammalian NLR proteins in myeloid lineages. Still, the function of pyrin domain-containing NLR proteins and NLRC4/NAIP as inflammasome components that drive interleukin-1β (IL-1β) and IL-18 maturation and secretion upon pathogen stimulation is well established. NOD1, NOD2, NLRP3, and NLRC4/NAIP act as bona fide pattern recognition receptors (PRRs) that sense microbe-associated molecular patterns (MAMPs) but also react to endogenous danger-associated molecular patterns (DAMPs)...
August 2016: Microbiology Spectrum
Jin Zhang, Linfeng Zheng, Xiangning Yuan, Chunyan Liu, Qiongjing Yuan, Feifei Xie, Sisi Qiu, Zhangzhe Peng, Yiting Tang, Jie Meng, Jiao Qin, Gaoyun Hu, Lijian Tao
Mefunidone is a new pyridone agent that attenuates renal tubulointerstitial fibrosis. However, the signaling pathways involved in the effect of mefunidone on renal tubulointerstitial fibrosis have not been well explained. Inflammatory response initiates and promotes renal tubulointerstitial fibrosis, and the inhibitor of nuclear factor kappa-B kinase beta (IKKβ) is a master regulator of inflammation. This study is determined to clarify the influence of mefunidone on renal inflammation and the phosphorylation of IKKβ...
October 8, 2016: International Journal of Biochemistry & Cell Biology
James D H Ong, Ashley Mansell, Michelle D Tate
The severity of influenza A virus (IAV) infection can range from asymptotic to mild to severe. Infections, such as those seen following outbreaks of avian IAV, are associated with hyperinflammatory responses and the development of fatal disease. There is a continual threat that a novel or pandemic IAV will circulate in humans with high rates of mortality. The neuronal apoptosis inhibitor protein, class 2 transcription activator of the MHC, heterokaryon incompatibility, telomerase-associated protein 1, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is an innate immune sensor that has been shown to be critical for the secretion of the potent proinflammatory cytokines, IL-1β and IL-18, as well as chemokine production and cellular inflammation in vivo following IAV infection...
October 5, 2016: Journal of Leukocyte Biology
Jie Ma, Wenjing Xiao, Junrui Wang, Juan Wu, Jiandong Ren, Jun Hou, Jianwen Gu, Kaihua Fan, Botao Yu
Increasing evidence has demonstrated that inflammatory response plays a crucial role in the pathogenesis of secondary injury following blast-induced traumatic brain injury (bTBI). Propofol, a lipid-soluble intravenous anesthetic, has been shown to possess therapeutic benefit during neuroinflammation on various brain injury models. Recent findings have proved that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome involved in the process of the inflammatory response following brain trauma, may probably be a promising target in the treatment of bTBI...
September 30, 2016: Inflammation
Xia Sun, Xiao Song, Li Zhang, Jian Sun, Xinbing Wei, Liya Meng, Jie An
Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors with a major role in innate immunity. Fourteen of the twenty-two human NLRs contain a pyrin domain and form the NLRP subfamily (NLRPs). Among NLRPs, NLRP2 is less well-understood in aspects of distribution and functions, especially in central nervous system (CNS). This study was the first to explore the expression of NLRP2 in central nervous system both under normal conditions and in ischemic stroke models...
October 28, 2016: Biochemical and Biophysical Research Communications
Daniel Peckham, Thomas Scambler, Sinisa Savic, Michael F McDermott
Immune-mediated autoinflammatory diseases are occupying an increasingly prominent position among the pantheon of debilitating conditions that afflict mankind. This review focuses on some of the key developments which have occurred since the original description of autoinflammatory disease in 1999, and focuses on underlying mechanisms that trigger autoinflammation. The monogenic autoinflammatory disease range has expanded considerably during that time, and now includes a broad spectrum of disorders, including relatively common conditions such as cystic fibrosis and subsets of systemic lupus erythematosus...
September 29, 2016: Journal of Pathology
Simon D Pouwels, Wouter H van Geffen, Marnix R Jonker, Huib A M Kerstjens, Martijn C Nawijn, Irene H Heijink
Previously, we observed increased serum levels of damage-associated molecular patterns (DAMPs) during COPD exacerbations. Here, gene expression of DAMP receptors was measured in peripheral blood neutrophils of COPD patients during stable disease and severe acute exacerbation. The expression of toll-like receptor (TLR)2, TLR4 and NLR family, pyrin domain-containing 3 (NLRP3) was significantly increased, while serum levels of the soluble form of the decoy receptor for advanced glycation end-product (sRAGE) were decreased during exacerbation...
September 27, 2016: Respirology: Official Journal of the Asian Pacific Society of Respirology
Milton Pereira, Panagiotis Tourlomousis, John Wright, Tom P Monie, Clare E Bryant
Interleukin-1β (IL-1β) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. Here we show that caspase recruitment domain-containing protein 9 (CARD9), a protein associated with induction of proinflammatory cytokines by fungi, has a negative role on IL-1β production during bacterial infection. Specifically, in response to activation of the nucleotide oligomerization domain receptor pyrin-domain containing protein 3 (NLRP3) by Salmonella infection, CARD9 negatively regulates IL-1β by fine-tuning pro-IL-1β expression, spleen tyrosine kinase (SYK)-mediated NLRP3 activation and repressing inflammasome-associated caspase-8 activity...
2016: Nature Communications
Yuan He, Hideki Hara, Gabriel Núñez
Members of the nucleotide-binding domain and leucine-rich repeat (LRR)-containing (NLR) family and the pyrin and HIN domain (PYHIN) family can form multiprotein complexes termed 'inflammasomes'. The biochemical function of inflammasomes is to activate caspase-1, which leads to the maturation of interleukin 1 beta (IL-1β) and IL-18 and the induction of pyroptosis, a form of cell death. Unlike other inflammasomes, the NLRP3 inflammasome can be activated by diverse stimuli. The importance of the NLRP3 inflammasome in immunity and human diseases has been well documented, but the mechanism and regulation of its activation remain unclear...
September 23, 2016: Trends in Biochemical Sciences
Haixiao Liu, Lei Zhao, Liang Yue, Bodong Wang, Xia Li, Hao Guo, Yihui Ma, Chen Yao, Li Gao, Jianping Deng, Lihong Li, Dayun Feng, Yan Qu
Pterostilbene (PTE), one of the polyphenols present in plants such as blueberries and grapes, has been suggested to have various effects, such as anti-oxidation, anti-apoptosis, and anti-cancer effects. Subarachnoid hemorrhage (SAH) is a severe neurological event known for its high morbidity and mortality. Recently, early brain injury (EBI) has been reported to play a significant role in the prognosis of patients with SAH. The present study aimed to investigate whether PTE could attenuate EBI after SAH was induced in C57BL/6 J mice...
September 24, 2016: Molecular Neurobiology
Franklin L Zhong, Ons Mamaï, Lorenzo Sborgi, Lobna Boussofara, Richard Hopkins, Kim Robinson, Ildikó Szeverényi, Takuya Takeichi, Reshmaa Balaji, Aristotle Lau, Hazel Tye, Keya Roy, Carine Bonnard, Patricia J Ahl, Leigh Ann Jones, Paul Baker, Lukas Lacina, Atsushi Otsuka, Pierre R Fournie, François Malecaze, E Birgitte Lane, Masashi Akiyama, Kenji Kabashima, John E Connolly, Seth L Masters, Vincent J Soler, Salma Samir Omar, John A McGrath, Roxana Nedelcu, Moez Gribaa, Mohamed Denguezli, Ali Saad, Sebastian Hiller, Bruno Reversade
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation...
September 22, 2016: Cell
H Latsoudis, M-F Mashreghi, J R Grün, H-D Chang, B Stuhlmueller, A Repa, I Gergiannaki, E Kabouraki, T Haeupl, A Radbruch, P Sidiropoulos, D Kardassis, D T Boumpas, G N Goulielmos
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute and self-limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival...
September 16, 2016: Journal of Cellular Physiology
Victoria Auerbuch
Inflammasome-associated innate immune receptors sense host-cell targeting by the type III secretion system (T3SS) of pathogenic Yersinia. In this issue of Cell Host & Microbe, Chung et al. (2016) show that the Yersinia T3SS effector protein YopM counteracts this recognition pathway by restricting the pyrin inflammasome, thus increasing bacterial fitness.
September 14, 2016: Cell Host & Microbe
Jijing Tian, Guoxiang Yang, Huan-Yuan Chen, Daniel K Hsu, Alexey Tomilov, Kristin A Olson, Ali Dehnad, Sarah R Fish, Gino Cortopassi, Bin Zhao, Fu-Tong Liu, M Eric Gershwin, Natalie J Török, Joy X Jiang
Macrophage activation is an important feature of primary biliary cholangitis (PBC) pathogenesis and other cholestatic liver diseases. Galectin-3 (Gal3), a pleiotropic lectin, is produced by monocytic cells and macrophages. However, its role in PBC has not been addressed. We hypothesized that Gal3 is a key to induce NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages and in turn to propagate proinflammatory IL-17 signaling. In liver tissues from patients with PBC and dnTGF-βRII mice, a model of autoimmune cholangitis, the expression of Gal3, NLRP3, and the adaptor protein adaptor apoptosis-associated speck-like protein was induced, with the downstream activation of caspase-1 and IL-1β...
September 14, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Dan Zhao, Yaqin Wu, Jiabao Zhuang, Chun Xu, Fuqiang Zhang
Inflammasomes have been reported to be present in periodontal inflammatory tissue, but the exact role of inflammasomes in periodontal inflammatory reactions especially those related to mechanical stimulations has not been clarified. In this study, it was shown that cyclic stretch activated the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 1 and 3 (NLRP1 and NLRP3) inflammasomes and induced the release of IL-1β and pyroptosis via a caspase-1-related mechanism in human periodontal ligament cells (HPDLCs)...
September 10, 2016: Oncotarget
Salih Coşkun, Sefer Varol, Hasan H Özdemir, Sercan Bulut Çelik, Metin Balduz, Mehmet Akif Camkurt, Abdullah Çim, Demet Arslan, Mehmet Uğur Çevik
Migraine pathogenesis involves a complex interaction between hormones, neurotransmitters, and inflammatory pathways, which also influence the migraine phenotype. The Mediterranean fever gene (MEFV) encodes the pyrin protein. The major role of pyrin appears to be in the regulation of inflammation activity and the processing of the cytokine pro-interleukin-1β, and this cytokine plays a part in migraine pathogenesis. This study included 220 migraine patients and 228 healthy controls. Eight common missense mutations of the MEFV gene, known as M694V, M694I, M680I, V726A, R761H, K695R, P369S, and E148Q, were genotyped using real-time polymerase chain reaction with 5' nuclease assays, which include sequence specific primers, and probes with a reporter dye...
2016: Neuropsychiatric Disease and Treatment
Shannon L Glisan, Caroline Ryan, Andrew P Neilson, Joshua D Lambert
Cranberry (Vaccinium macrocarpon) consumption has been associated with health beneficial effects. Nonalcoholic fatty liver disease (NAFLD) is a comorbidity of obesity. In the present study, we investigated the effect of a polyphenol-rich cranberry extract (CBE) on hepatic inflammation in high fat (HF)-fed obese C57BL/6J mice. Following dietary treatment with 0.8% CBE for 10 weeks, we observed no change in body weight or visceral fat mass in CBE-supplemented mice compared to HF-fed control mice. We did observe a significant decrease in plasma alanine aminotransferase (31%) and histological severity of NAFLD (33% decrease in area of involvement, 29% decrease in lipid droplet size) compared to HF-fed controls...
August 4, 2016: Journal of Nutritional Biochemistry
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