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Wei Chi, Xia Hua, Xin Chen, Fang Bian, Xiaoyong Yuan, Lili Zhang, Xiaoran Wang, Ding Chen, Ruzhi Deng, Zhijie Li, Yizhi Liu, Cintia S de Paiva, Stephen C Pflugfelder, De-Quan Li
The concept of innate immunity has been expanded to recognize environmental pathogens other than microbial components. However, whether and how the innate immunity is initiated by epithelium in response to environmental physical challenges such as low humidity and high osmolarity in an autoimmune disease, dry eye, is still largely unknown. Using two experimental dry eye models, primary human corneal epithelial cultures exposed to hyperosmolarity and mouse ocular surface facing desiccating stress, we uncovered novel innate immunity pathway by ocular surface epithelium, where oxidized mitochondrial DNA induces imbalanced activation of NLRP3/NLRP6 inflammasomes via stimulation of caspase-8 and BRCC36 in response to environmental stress...
February 23, 2017: Journal of Autoimmunity
Maayan Levy, Hagit Shapiro, Christoph A Thaiss, Eran Elinav
NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, regulates inflammation and host defense against microorganisms. Similar to other NLRs, NLRP6 not only participates in inflammasome formation, but is also involved in nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling regulation and facilitation of gastrointestinal antiviral effector functions. Additionally, NLRP6 contributes to the regulation of mucus secretion and antimicrobial peptide production, thereby impacting intestinal microbial colonization and associated microbiome-related infectious, autoinflammatory, metabolic, and neoplastic diseases...
April 2017: Trends in Immunology
M Mamantopoulos, F Ronchi, F Van Hauwermeiren, S Vieira-Silva, B Yilmaz, L Martens, Y Saeys, S Drexler, A Yazdi, J Raes, M Lamkanfi, K McCoy, A Wullaert
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
Jia-Qi Chu, Ge Shi, Yi-Ming Fan, In-Wook Choi, Guang-Ho Cha, Yu Zhou, Young-Ha Lee, Juan-Hua Quan
Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1β. To elucidate the role of inflammasome components in T. gondii-infected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine IL-1β secretion...
December 2016: Korean Journal of Parasitology
Rajendra Karki, Si Ming Man, Thirumala-Devi Kanneganti
Inflammation affects all stages of tumorigenesis. A key signaling pathway leading to acute and chronic inflammation is through activation of the caspase-1 inflammasome. Inflammasome complexes are assembled on activation of certain nucleotide-binding domain, leucine-rich repeat-containing proteins (NLR), AIM2-like receptors, or pyrin. Of these, NLRP1, NLRP3, NLRC4, NLRP6, and AIM2 influence the pathogenesis of cancer by modulating innate and adaptive immune responses, cell death, proliferation, and/or the gut microbiota...
February 2017: Cancer Immunology Research
Philipp Prager, Margrit Hollborn, Anja Steffen, Peter Wiedemann, Leon Kohen, Andreas Bringmann
BACKGROUND: Systemic hypertension is a risk factor of age-related macular degeneration (AMD), a chronic inflammatory disease. Acute hypertension is caused by increased extracellular osmolarity after intake of dietary salt (NaCl). We determined in cultured human retinal pigment epithelial (RPE) cells whether high extracellular NaCl alters the gene expression of inflammasome-associated proteins, and whether autocrine/paracrine purinergic (P2) receptor signaling contributes to the NaCl-induced NLRP3 gene expression...
2016: PloS One
Pedro Bullón, Jose Manuel Navarro
Endometriosis remains a challenging condition for clinicians to treat. To improve our results we have to develop new treatment strategies based on pathophysiological mechanisms targeting the etiologic and pathogenic processes involved. It is essential to understand the inflammatory reaction and immunity incorporating the new molecular concepts. Inflammasome has been described as a multiprotein complex and is considered a key regulator of the innate and adaptive host response that surveys the cytosol and other compartments into the cell...
July 8, 2016: Current Drug Targets
S S Seregin, N Golovchenko, B Schaf, J Chen, K A Eaton, G Y Chen
NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of interleukin (IL)-18 and is important for protecting mice against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6C(hi) inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation...
March 2017: Mucosal Immunology
George M H Birchenough, Elisabeth E L Nyström, Malin E V Johansson, Gunnar C Hansson
Innate immune signaling pathways contribute to the protection of host tissue when bacterially challenged. Colonic goblet cells are responsible for generating the two mucus layers that physically separate the luminal microbiota from the host epithelium. Analysis of colonic tissues from multiple mouse strains allowed us to identify a "sentinel" goblet cell (senGC) localized to the colonic crypt entrance. This cell nonspecifically endocytoses and reacts to the TLR2/1, TLR4, and TLR5 ligands by activating the Nlrp6 inflammasome downstream of TLR- and MyD88-dependent Nox/Duox reactive oxygen species synthesis...
June 24, 2016: Science
Ann M Janowski, Fayyaz S Sutterwala
Pattern recognition receptors, including members of the NLR and PYHIN families, are essential for recognition of both pathogen- and host-derived danger signals. A number of molecules in these families are capable of forming multiprotein complexes termed inflammasomes that result in the activation of caspase-1. In addition to NLRP1, NLRP3, NLRC4, and AIM2, which form well-described inflammasome complexes, IFI16, NLRP6, NLRP7, NLRP12, and NLRC5 have also been proposed to form inflammasomes under specific conditions...
2016: Methods in Molecular Biology
A Pontillo, P Bricher, V N C Leal, S Lima, P R E Souza, S Crovella
PROBLEM: Only a small proportion of HPV+ women develop virus-associated lesions and cervical cancer, suggesting that other factors are involved in HPV+ keratinocyte transformation. Immune response plays an important role in clearing HPV infection, and host genetic variants resulting in defective immune response have been associated with virus persistence and/or cervical cancer. Considering that genetic variations in inflammasome genes were previously associated with viral infection and cancer development, the present study investigates selected single nucleotide polymorphisms (SNPs) in inflammasome genes as a possible risk factor for HPV infection susceptibility and/or for progression to cervical cancer...
September 2016: Journal of Medical Virology
Qi Yang, Jianwei Wang, Ran Liu, Zhiqiang Wang, Yufeng Li, Yifan Zhang, Xiaohua Hao, Yubo Huang, Wen Xie, Hongshan Wei
Magnesium isoglycyrrhizinate (MGL) is a new stereoisomer of glycyrrhizic acid, which is clinically used as a hepatoprotective medicine with more potent effects and less side effects than glycyrrhizic acid. This study was designed to evaluate the protective effects and possible mechanism of MGL against concanavalin A (Con A)-induced autoimmune hepatitis. Hepatitis was induced by Con A in C57/6J mice with or without MGL administration; injury score and serum ALT were evaluated. The CD4(+) T-cells were isolated from splenocytes and challenged with Con A after coculturing with MGL...
2016: Drug Design, Development and Therapy
Keren Bahar Halpern, Inbal Caspi, Doron Lemze, Maayan Levy, Shanie Landen, Eran Elinav, Igor Ulitsky, Shalev Itzkovitz
mRNA is thought to predominantly reside in the cytoplasm, where it is translated and eventually degraded. Although nuclear retention of mRNA has a regulatory potential, it is considered extremely rare in mammals. Here, to explore the extent of mRNA retention in metabolic tissues, we combine deep sequencing of nuclear and cytoplasmic RNA fractions with single-molecule transcript imaging in mouse beta cells, liver, and gut. We identify a wide range of protein-coding genes for which the levels of spliced polyadenylated mRNA are higher in the nucleus than in the cytoplasm...
December 29, 2015: Cell Reports
Misagh Alipour, Deenaz Zaidi, Rosica Valcheva, Juan Jovel, Inés Martínez, Consolato Sergi, Jens Walter, Andrew L Mason, Gane Ka-Shu Wong, Levinus A Dieleman, Matthew W Carroll, Hien Q Huynh, Eytan Wine
BACKGROUND AND AIMS: Ulcerative colitis [UC] is associated with colonic mucosa barrier defects and bacterial dysbiosis, but these features may simply be the result of inflammation. Therefore, we sought to assess whether these features are inherently abrogated in the terminal ileum [TI] of UC patients, where inflammation is absent. METHODS: TI biopsies from paediatric inflammatory bowel disease [IBD] subsets [Crohn's disease [CD; n = 13] and UC [n = 10]], and non-IBD disease controls [n = 12] were histologically graded, and alcian blue/periodic acid-Schiff stained biopsies were quantified...
April 2016: Journal of Crohn's & Colitis
Maayan Levy, Christoph A Thaiss, David Zeevi, Lenka Dohnalová, Gili Zilberman-Schapira, Jemal Ali Mahdi, Eyal David, Alon Savidor, Tal Korem, Yonatan Herzig, Meirav Pevsner-Fischer, Hagit Shapiro, Anette Christ, Alon Harmelin, Zamir Halpern, Eicke Latz, Richard A Flavell, Ido Amit, Eran Segal, Eran Elinav
Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles...
December 3, 2015: Cell
Penghua Wang, Shu Zhu, Long Yang, Shuang Cui, Wen Pan, Ruaidhri Jackson, Yunjiang Zheng, Anthony Rongvaux, Qiangming Sun, Guang Yang, Shandian Gao, Rongtuan Lin, Fuping You, Richard Flavell, Erol Fikrig
The nucleotide-binding oligomerization domain-like receptor (Nlrp) 6 maintains gut microbiota homeostasis and regulates antibacterial immunity. We now report a role for Nlrp6 in the control of enteric virus infection. Nlrp6(-/-) and control mice systemically challenged with encephalomyocarditis virus had similar mortality; however, the gastrointestinal tract of Nlrp6(-/-) mice exhibited increased viral loads. Nlrp6(-/-) mice orally infected with encephalomyocarditis virus had increased mortality and viremia compared with controls...
November 13, 2015: Science
Francis M Hughes, David P Turner, J Todd Purves
PURPOSE: The urothelium is a frontline sensor of the lower urinary tract, sampling the bladder lumen and stimulating an immune response to infectious and noxious agents. Pattern recognition receptors (PRRs) recognize such agents and coordinate the innate response, often by forming inflammasomes that activate caspase-1 and the release of interleukin-1. We have shown the presence of one PRR (NLRP3) in the urothelia and its central role in the inflammatory response to cyclophosphamide. The purpose of this study was to (1) assess the likely range of the PPR response by assessing the repertoire present in the rat bladder and (2) determine the utility of the MYP3 rat urothelia cell line for in vitro studies by assessing its PPR repertoire and functional responsiveness...
December 2015: International Urology and Nephrology
Rongrong Liu, Agnieszka D Truax, Liang Chen, Peizhen Hu, Zengshan Li, Jun Chen, Chaojun Song, Lihua Chen, Jenny Pan-Yun Ting
NLRs (nucleotide-binding domain leucine-rich repeat proteins or NOD-like receptors) are regulators of inflammation and immunity. A subgroup of NLRs and the innate immune receptor, AIM2 (absent-in-melanoma 2), can induce the assembly of a large caspase-1 activating complex called the inflammasome. Other NLRs regulate key signaling pathways such as NF-kB and MAPK. Since inflammation is a central component of colorectal cancer (CRC), this work was undertaken to analyze NLR and AIM2 expression in human CRC by combining bioinformatics analysis and experimental verification using clinical tissue samples...
October 20, 2015: Oncotarget
Elke Ydens, Dieter Demon, Guillaume Lornet, Vicky De Winter, Vincent Timmerman, Mohamed Lamkanfi, Sophie Janssens
BACKGROUND: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1β and IL-18. However, their role in response to injury in the nervous system is less understood. METHODS: In this study, we investigated the expression profile of major inflammasome components in the peripheral nervous system (PNS) and explored the physiological role of different Nlrs upon acute nerve injury in mice...
2015: Journal of Neuroinflammation
Milena Nasi, Sara De Biasi, Elena Bianchini, Margherita Digaetano, Marcello Pinti, Lara Gibellini, Simone Pecorini, Gianluca Carnevale, Giovanni Guaraldi, Vanni Borghi, Cristina Mussini, Andrea Cossarizza
OBJECTIVE: Few studies have investigated the importance of different components of the inflammasome system and of innate mitochondrial sensing (IMS) pathways in HIV infection and its treatment. We analysed the expression of several components of the inflammasome and of the IMS in HIV-positive patients taking successful combination antiretroviral therapy (cART). METHODS: We enrolled 20 HIV-positive patients under cART, who achieved viral suppression since at least 10 months and 20 age and sex-matched healthy donors...
September 24, 2015: AIDS
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