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Berteau Florian, Rouviere Bénédicte, Delluc Aurélien, Nau Alice, Le Berre Rozenn, Sarrabay Guillaume, Touitou Isabelle, Claire de Moreuil
INTRODUCTION: Behçet disease (BD) is a systemic vasculitis involving vessels from any size with various clinical features. Most BD cases are multifactorial and associated with the HLA B51 antigen. In rare and severe early onset cases, dominant Mendelian transmission has been linked to mutations in the TNFAIP3 gene encoding A20. Herein, we propose a systematic review of the literature about the haploinsufficiency A20 (HA20) published cases. SYSTEMATIC REVIEW: Our review of the 45 cases of HA20 from literature highlights the similarities and the differences between this genetic auto-inflammatory disease and classical BD...
June 8, 2018: Autoimmunity Reviews
Christoph Schneider, Claire E O'Leary, Jakob von Moltke, Hong-Erh Liang, Qi Yan Ang, Peter J Turnbaugh, Sridhar Radhakrishnan, Michael Pellizzon, Averil Ma, Richard M Locksley
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome...
May 23, 2018: Cell
Deenaz Zaidi, Hien Q Huynh, Matthew W Carroll, Shairaz Baksh, Eytan Wine
Purpose: A significant feature of pediatric inflammatory bowel diseases (IBD), which include Crohn disease (CD), and ulcerative colitis (UC), is failure to suppress inflammation. The inability to regulate inflammation renders a major challenge toward establishing effective treatments in IBD. Nuclear factor kappa-light-chain-enhancer of activated B-cells-induced inflammation is inhibited by A20 through interactions with TAX1BP1 (Tax1-binding protein 1) and A20-binding inhibitor of NF-κβ activation (ABIN)-1 (A20 binding and inhibitor of NF-κβ) and upon phosphorylation by inhibitor of nuclear factor kappa-β kinase subunit beta (IKKβ), which stabilizes it...
2018: Clinical and Experimental Gastroenterology
Cuiqing Ma, Xue Gao, Shuhui Wu, Ling Zhang, Jiachao Wang, Zhengzheng Zhang, Zhiyan Yao, Xiaotian Song, Wenjian Li, Xiurong Wang, Huidong Feng, Lin Wei
Group A streptococcus (GAS), a common pathogen, is able to escape host immune attack and thus survive for longer periods of time. One of the mechanisms used by GAS is the upregulated expression of immunosuppressive molecules, which leads to a reduction in the production of inflammatory cytokines in immune cells. In the present study, we found that macrophages produced lower levels of proinflammatory cytokines (IL-1β, TNF-α, IL-6) when challenged with GAS than they did when challenged with Escherichia coli ( E...
2018: Frontiers in Cellular and Infection Microbiology
Sebastian Dorn, Christian Schoergenhofer, Michael Krainer, Markus Müller, Bernd Jilma
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known to activate the canonical NF-κB pathway similar to TNF. The exact mechanism of the entire signaling cascade is still under investigation. The involvement of linear ubiquitylation as upregulating component has already been shown recently in some cell lines, but not in human embryonic kidney 293 (HEK293) cells. The downregulating function of the ABIN-1 (A20 binding and inhibitor of NF-κB) as linear ubiquitylation antagonist has been shown in combination with some NF-κB-inducing pathways, but not with TRAIL...
2018: BioResearch Open Access
Asher Maroof, Dhavalkumar D Patel
No abstract text is available yet for this article.
May 31, 2018: Journal of Allergy and Clinical Immunology
Annemarie Steiner, Cassandra R Harapas, Seth L Masters, Sophia Davidson
PURPOSE OF REVIEW: The nuclear factor κB (NF-κB) pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways can cause disease and are the focus of this review. RECENT FINDINGS: The linear ubiquitin chain assembly complex (LUBAC) is a trimer made up of HOIL-1L, SHARPIN, and the catalytic subunit HOIP. Loss of function mutations in HOIL-1L and HOIP result in largely overlapping phenotypes, characterized by multi-organ autoinflammation, immunodeficiency, and amylopectinosis...
May 30, 2018: Current Rheumatology Reports
Hanni Uusi-Kerttula, James A Davies, Jill Thompson, Phonphimon Wongthida, Laura Evgin, Kevin G Shim, Angela Bradshaw, Alexander T Baker, Pierre J Rizkallah, Rachel Jones, Louise Hanna, Emma Hudson, Richard Vile, John D Chester, Alan L Parker
PURPOSE:  Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for manipulability and tolerance of transgenes. Poor tumour-selectivity, off-target sequestration and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumour selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but non-detectable in healthy tissues. EXPERIMENTAL DESIGN:  Ad5NULL -A20 harbours mutations in each major capsid protein to preclude uptake via all native pathways...
May 24, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
T Kawahara, N Hanzawa, M Sugiyama
Lactobacillus strains, a major group of lactic acid bacteria, are representative food microorganisms that have many potential beneficial effects via their interactions with immune and intestinal epithelial cells. However, little is known about the effect of Lactobacillus strains on atopic dermatitis via keratinocytes, which comprise the physical barrier of the skin. In this study, we report that Lactobacillus strains have a significant suppressive effect on tumour necrosis factor (TNF)-α-induced expression and production of thymus and activation-regulated chemokine (TARC), a T helper 2 cell chemokine responsible for atopic dermatitis, in human keratinocytes...
May 25, 2018: Beneficial Microbes
Dheeraj Soni, Dong-Mei Wang, Sushil C Regmi, Manish Mittal, Stephen M Vogel, Dirk Schlüter, Chinnaswamy Tiruppathi
Vascular endothelial cadherin (VE-cad) expression at endothelial adherens junctions (AJs) regulates vascular homeostasis. Here we show that endothelial A20 is required for VE-cad expression at AJs to maintain and repair the injured endothelial barrier. In endothelial cell (EC)-restricted Tnfaip3 (A20) knockout ( A20 ∆EC ) mice, LPS challenge caused uncontrolled lung vascular leak and persistent sequestration of polymorphonuclear neutrophil (PMNs). Importantly, A20 ∆EC mice exhibited drastically reduced VE-cad expression in lungs compared with wild-type counterparts...
2018: Cell Death Discovery
Shi Wanchao, Ma Chen, Su Zhiguo, Xie Futang, Shi Mengmeng
The present study was designed to investigate the protective effects and mechanism of inactivated lactobacillus (ILA) on cerebral ischemia reperfusion injury (CIRI) in rats. In this experiment, 30 male Sprague Dawley rats were randomly divided into control group, IRI groups, and ILA group. A middle cerebral artery occlusion and reperfusion model was prepared. The rats were killed after 24 hours of recovery of blood flow of cerebral ischemia resulting from 60-min occlusion. The cerebral infarction volume and neurological scores were assayed by staining and behavioral observation...
2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Sofie Voet, Conor Mc Guire, Nora Hagemeyer, Arne Martens, Anna Schroeder, Peter Wieghofer, Carmen Daems, Ori Staszewski, Lieselotte Vande Walle, Marta Joana Costa Jordao, Mozes Sze, Hanna-Kaisa Vikkula, Delphine Demeestere, Griet Van Imschoot, Charlotte L Scott, Esther Hoste, Amanda Gonçalves, Martin Guilliams, Saskia Lippens, Claude Libert, Roos E Vandenbroucke, Ki-Wook Kim, Steffen Jung, Zsuzsanna Callaerts-Vegh, Patrick Callaerts, Joris de Wit, Mohamed Lamkanfi, Marco Prinz, Geert van Loo
Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency...
May 23, 2018: Nature Communications
Norah A Alturki, Scott McComb, Ardeshir Ariana, Dikchha Rijal, Robert G Korneluk, Shao-Cong Sun, Emad Alnemri, Subash Sad
Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins...
May 22, 2018: Cell Death & Disease
Cuifang Zheng, Ying Huang, Ziqing Ye, Yuhuan Wang, Zifei Tang, Junping Lu, Jie Wu, Ying Zhou, Lin Wang, Zhiheng Huang, Haowei Yang, Aijuan Xue
Background : Mutations in tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key player in the negative feedback regulation of nuclear factor-κB signaling, have recently been recognized as leading to early onset autoinflammatory and autoimmune syndrome. Here, we have reported the phenotypes of 3 infantile onset intractable inflammatory bowel disease (IBD) patients with TNFAIP3 mutations and reviewed previously reported cases to establish phenotypic features associated with TNFAIP3 monogenicity...
May 17, 2018: Inflammatory Bowel Diseases
Qian Chen, Min-Hui Pang, Xiao-Hong Ye, Guang Yang, Chen Lin
BACKGROUND: Acute T-lymphocyte leukaemia is a form of haematological malignancy with abnormal activation of NF-κB pathway, which results in high expression of A20 and ABIN1, which constitute a negative feedback mechanism for the regulation of NF-κB activation. Clinical studies have found that acute T-lymphocyte leukaemia patients are susceptible to Toxoplasma gondii infection; however, the effect of T. gondii on the proliferation and apoptosis of human leukaemia T-cells remains unclear...
May 18, 2018: Parasites & Vectors
C V Harper, D J Woodcock, C Lam, M Garcia-Albornoz, A Adamson, L Ashall, W Rowe, P Downton, L Schmidt, S West, D G Spiller, D A Rand, M R H White
NF-κB signaling plays a pivotal role in control of the inflammatory response. We investigated how the dynamics and function of NF-κB were affected by temperature within the mammalian physiological range (34 °C to 40 °C). An increase in temperature led to an increase in NF-κB nuclear/cytoplasmic oscillation frequency following Tumor Necrosis Factor alpha (TNFα) stimulation. Mathematical modeling suggested that this temperature sensitivity might be due to an A20-dependent mechanism, and A20 silencing removed the sensitivity to increased temperature...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ole Audun Werner Haabeth, Marte Fauskanger, Melanie Manzke, Katrin U Lundin, Alexandre Corthay, Bjarne Bogen, Anders Aune Tveita
Tumor-specific CD4+ T cells have been shown to mediate efficient anti-tumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)-expressing tumor cells or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4+ T cells reactive against an epitope within the Ig light chain variable region of a murine B cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II-restricted antigen presentation on tumor cells alone was required for rejection...
May 11, 2018: Cancer Research
Emmy Van Quickelberghe, Arne Martens, Ludger J E Goeminne, Lieven Clement, Geert van Loo, Kris Gevaert
A20 is a negative regulator of NF-κB signaling, it controls inflammatory responses and ensures tissue homeostasis. A20 is thought to restrict NF-κB activation both by its ubiquitin-editing activity as well as by its non-enzymatic activities. Besides its role in NF-κB signaling, A20 also acts as a protective factor inhibiting apoptosis and necroptosis. Because of the ability of A20 to both ubiquitinate and deubiquitinate substrates, and its involvement in many cellular processes, we hypothesized that deletion of A20 might generally impact on protein levels, thereby disrupting cellular signaling...
May 7, 2018: Journal of Proteome Research
Sinéad Kinsella, Michael Fichtner, Orla Watters, Hans-Georg König, Jochen H M Prehn
BACKGROUND: Chronic pro-inflammatory signaling propagates damage to neural tissue and affects the rate of disease progression. Increased activation of Toll-like receptors (TLRs), master regulators of the innate immune response, is implicated in the etiology of several neuropathologies including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Previously, we identified that the Bcl-2 family protein BH3-interacting domain death agonist (Bid) potentiates the TLR4-NF-κB pro-inflammatory response in glia, and specifically characterized an interaction between Bid and TNF receptor associated factor 6 (TRAF6) in microglia in response to TLR4 activation...
May 2, 2018: Journal of Neuroinflammation
Brooke N Nakamura, Alison Glazier, Michael G Kattah, Bao Duong, Yanxia Jia, Daniel Campo, Ling Shao
A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice. The underlying mechanisms for this phenomenon are unclear. To study this, we first generated A20 knockout cell lines by genome-editing techniques...
2018: PloS One
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