DOCSLIB.ORG

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-Κb

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-Κb Loss of NLRX1 Exacerbates Neural Tissue Damage and NF- κB Signaling following Brain Injury This information is current as Michelle H. Theus, Thomas Brickler, Armand L. Meza, of October 3, 2021. Sheryl Coutermarsh-Ott, Amanda Hazy, Denis Gris and Irving C. Allen J Immunol 2017; 199:3547-3558; Prepublished online 9 October 2017; doi: 10.4049/jimmunol.1700251 http://www.jimmunol.org/content/199/10/3547 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/10/07/jimmunol.170025 Material 1.DCSupplemental http://www.jimmunol.org/ References This article cites 65 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/199/10/3547.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 3, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-kB Signaling following Brain Injury Michelle H. Theus,*,1 Thomas Brickler,*,2 Armand L. Meza,*,†,2 Sheryl Coutermarsh-Ott,*,1 Amanda Hazy,* Denis Gris,‡ and Irving C. Allen*,1 Traumatic and nontraumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity, and free-radical release, contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we used Nlrx12/2 mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). In this article, we show that Nlrx12/2 mice exhibited significantly larger brain lesions and increased motor deficits following CCI Downloaded from injury. Mechanistically, our data indicate that the NF-kB signaling cascade is significantly upregulated in Nlrx12/2 animals. This upregulation is associated with increased microglia and macrophage populations in the cortical lesion. Using a mouse neuroblas- toma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-kB signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host–pathogen http://www.jimmunol.org/ defense and identify this highly novel NLR as a significant modulator of brain injury progression. The Journal of Immunology, 2017, 199: 3547–3558. raumatic brain injury (TBI) is a complex neurologic con- brain. These events may or may not involve injury to the skull or dition that has emerged as an important cause of morbidity overlying tissues. Conversely, nontraumatic brain injuries have a T and mortality in the adolescent and young adult pop- wide range of causes but are not directly associated with physical ulations. It is defined differently throughout the literature but is trauma. Examples of nontraumatic brain injury can include brain generally accepted as any external force that causes injury to the tumors, meningitis, hypoxic/anoxic brain injury, stroke, or aneu- rysm. In traumatic and nontraumatic brain injury, the resulting by guest on October 3, 2021 morbidity and mortality seen clinically are not typically due to the *Department of Biomedical Sciences and Pathobiology, Virginia–Maryland College actual primary injury itself, but rather the secondary changes that † of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061; Department of Neu- occur in the brain as a result of the injury. These secondary roscience, Virginia Tech, Blacksburg, VA 24061; and ‡Programme d’Immunologie, Faculte´ de Me´decine et des Sciences de la Sante´,Universite´ de Sherbrooke, Sherbrooke, changes are associated with the activation of the innate and Quebec J1H 5N4, Canada adaptive immune system and include inflammation, infiltration of 1M.H.T., S.C.-O., and I.C.A. contributed equally to this work. immune cells, release of excitatory neurotransmitters, cerebral 2T.B. and A.L.M. contributed equally to this work. edema, vasospasm, ischemia, hypoxia, free-radical damage, and ORCIDs: 0000-0001-6485-2104 (M.H.T.); 0000-0002-1580-4808 (T.B.); 0000-0001- others (1–3). A great deal of research has looked into the role of 9573-5250 (I.C.A.). the adaptive immune system in brain injury and how it can mod- Received for publication February 21, 2017. Accepted for publication September 7, ulate these various secondary processes. However, only relatively 2017. recently have researchers begun to focus on the role of the innate This work was supported by National Institute of Neurological Disease and Stroke Awards NS096281 and NS081623. Student work was supported by National Institute immune system (1). The majority of studies have been focused on of Allergy and Infectious Diseases Animal Model Research for Veterinarians Train- the role of microglial cells in the progression of the injury, because ing Grant T32-OD010430 (to S.C.-O.). Student support throughout this project was they are the predominant innate immune cell type in the brain (2). also provided by the Virginia Tech Initiative for Maximizing Student Development program (GM0727-09) and the Virginia Tech Post-Baccalaureate Research and Ed- Somewhat similar to macrophages, microglial cells express a di- ucation Program (GM066534-14). The content is solely the responsibility of the verse variety of pattern recognition receptors (PRRs) that modulate authors and does not necessarily represent the official views of the National Institutes of Health or any other funding agency. their response to injury and drive many of the critical secondary Address correspondence and reprint requests to Dr. Michelle H. Theus and Dr. Irving changes seen in the brain following injury (2). C. Allen, Virginia Tech, Virginia–Maryland College of Veterinary Medicine, Depart- PRRs are proteins associated with plasma and endosomal ment of Biomedical Sciences, IDRF 140, Duckpond Drive, Blacksburg, VA 24061. membranes, as well as the cytosol itself. These receptors and sen- E-mail addresses: [email protected] (M.H.T.) and [email protected] (I.C.A.) sors are responsible for recognition of various foreign and host mo- The online version of this article contains supplemental material. lecular motifs (known as damage-associated molecular patterns or Abbreviations used in this article: CCI, controlled cortical impact; EAE, experimen- pathogen-associated molecular patterns). Once these proteins bind tal autoimmune encephalomyelitis; GFAP, glial fibrillary acid protein; IHC, immu- nohistochemistry; IPA, Ingenuity Pathway Analysis; NLR, NOD-like receptor; PI, or sense their respective ligands, they are responsible for initiating propidium iodide; PRR, pattern recognition receptor; ROS, reactive oxygen species; a variety of cellular responses, including the activation of key in- shRNA, short hairpin RNA; TBI, traumatic brain injury. flammatory signaling pathways, such as the NF-kB signaling cas- Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 cade. NF-kB signaling has previously been shown to be important www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700251 3548 NLRX1 PROTECTS AGAINST BRAIN INJURY in the pathogenesis of brain injury. For example, Lian et al. (4) Materials and Methods showed that mice lacking IkBɑ,anNF-kB inhibitory protein, Animals showed significantly increased neuroinflammation when assessed in 2 2 The generation and characterization of Nlrx1 / mice have been previ- a model of TBI. Moreover, in another TBI model, suppressing the ously described (15). All mice were maintained on the C57BL/6J back- NF-kB signaling pathway through exogenous VEGI treatment at- ground. All animals used in experiments were male and between 2 and tenuated brain injury (5). Thus, these studies illustrate that unre- 4 mo of age. C57BL/6J and Nlrx12/2 mice were maintained as separate stricted NF-kB signaling is an important component in the colonies. All studies involving mice were repeated at least three inde- pathophysiology of brain injury. pendent times, with three to seven mice per genotype and treatment group. All experiments were conducted in accordance with the National Institutes NOD-like receptors (NLRs) are intracellular PRRs that are of Health’s Guide for the Care and Use of Laboratory Animals and were generally classified as either inflammasome-forming NLRs or
Load more

Recommended publications
  • The Role of Vimentin and the NLRP3 Inflammasome in Influenza a Infection
    The Role of Vimentin and the NLRP3 Inflammasome in Influenza A Infection A Senior Thesis Presented to The Faculty of the Department of Molecular Biology, Colorado College By Maggie Turner Bachelor of Arts Degree in Molecular Biology April 28, 2017 ________________________ Dr. Olivia Hatton Primary Thesis Advisor __________________________ Dr. Sara Hanson Secondary Thesis Advisor ABSTRACT Infection with Influenza A virus (IAV) continues to cause morbidity and mortality in children across the globe, in part due to the excessive inflammatory response during pathogen clearance. Using a murine model of IAV infection, this study focuses on the role of the innate immune system in IAV infection through the scope of NLRP3 inflammasome protein activation and assembly. We were able to detect the presence of the NLRP3-inflammasome target proteins ASC, Pro-caspase-1, NLRP3, RIG-1, and IL- 1β in both juvenile and adult mice. Notably, we found significantly increased levels of ASC and RIG-1 protein in juveniles compared to adults. This suggests that ASC and RIG-1 are related to the observed excessive inflammatory response upon IAV infection in juveniles. To examine NLRP3-inflammasome assembly, we created multiple mutant constructs of the inflammasome scaffolding protein Vimentin as well as vimentin-/- cells. IL-1β production was greatly inhibited in vimentin-/- cells compared to the wild type upon activation of the NLRP3 inflammasome. The same trend was seen when only the head region of the protein was present. We suggest that the intermediate filament (IF) Vimentin serves as a protein scaffold for inflammasome assembly, and that expression of Vimentin is a necessary checkpoint in the innate immune response.
    [Show full text]
  • The Expression of NOD2, NLRP3 and NLRC5 and Renal Injury in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
    Wang et al. J Transl Med (2019) 17:197 https://doi.org/10.1186/s12967-019-1949-5 Journal of Translational Medicine RESEARCH Open Access The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis Luo‑Yi Wang1,2,3, Xiao‑Jing Sun1,2,3, Min Chen1,2,3* and Ming‑Hui Zhao1,2,3,4 Abstract Background: Nucleotide‑binding oligomerization domain (NOD)‑like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the infammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti‑neutrophil cytoplasmic antibody (ANCA)‑associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide‑binding oligomerization domain con‑ taining protein 2 (NOD2), NOD‑like receptor family pyrin domain containing 3 (NLRP3) and NOD‑like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters. Methods: Thirty‑four AAV patients in active stage were recruited. Their renal specimens were processed with immu‑ nohistochemistry to assess the expression of three NLRs, and with double immunofuorescence to detect NLRs on intrinsic and infltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associa‑ tions between expression of NLRs and clinicopathological parameters were analyzed. Results: The expression of NOD2, NLRP3 and NLRC5 was signifcantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co‑localized with podocytes and infltrating infammatory cells.
    [Show full text]
  • Genetic Diagnosis in First Or Second Trimester Pregnancy Loss Using Exome Sequencing: a Systematic Review of Human Essential Genes
    Journal of Assisted Reproduction and Genetics (2019) 36:1539–1548 https://doi.org/10.1007/s10815-019-01499-6 REVIEW Genetic diagnosis in first or second trimester pregnancy loss using exome sequencing: a systematic review of human essential genes Sarah M. Robbins1,2 & Matthew A. Thimm3 & David Valle1 & Angie C. Jelin4 Received: 18 December 2018 /Accepted: 29 May 2019 /Published online: 4 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose Non-aneuploid recurrent pregnancy loss (RPL) affects approximately 100,000 pregnancies worldwide annually. Exome sequencing (ES) may help uncover the genetic etiology of RPL and, more generally, pregnancy loss as a whole. Previous studies have attempted to predict the genes that, when disrupted, may cause human embryonic lethality. However, predictions by these early studies rarely point to the same genes. Case reports of pathogenic variants identified in RPL cases offer another clue. We evaluated known genetic etiologies of RPL identified by ES. Methods We gathered primary research articles from PubMed and Embase involving case reports of RPL reporting variants identified by ES. Two authors independently reviewed all articles for eligibility and extracted data based on predetermined criteria. Preliminary and amended analysis isolated 380 articles; 15 met all inclusion criteria. Results These 15 articles described 74 families with 279 reported RPLs with 34 candidate pathogenic variants in 19 genes (NOP14, FOXP3, APAF1, CASP9, CHRNA1, NLRP5, MMP10, FGA, FLT1, EPAS1, IDO2, STIL, DYNC2H1, IFT122, PA DI6, CAPS, MUSK, NLRP2, NLRP7) and 26 variants of unknown significance in 25 genes. These genes cluster in four essential pathways: (1) gene expression, (2) embryonic development, (3) mitosis and cell cycle progression, and (4) inflammation and immunity.
    [Show full text]
  • Bayesian Hierarchical Modeling of High-Throughput Genomic Data with Applications to Cancer Bioinformatics and Stem Cell Differentiation
    BAYESIAN HIERARCHICAL MODELING OF HIGH-THROUGHPUT GENOMIC DATA WITH APPLICATIONS TO CANCER BIOINFORMATICS AND STEM CELL DIFFERENTIATION by Keegan D. Korthauer A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Statistics) at the UNIVERSITY OF WISCONSIN–MADISON 2015 Date of final oral examination: 05/04/15 The dissertation is approved by the following members of the Final Oral Committee: Christina Kendziorski, Professor, Biostatistics and Medical Informatics Michael A. Newton, Professor, Statistics Sunduz Kele¸s,Professor, Biostatistics and Medical Informatics Sijian Wang, Associate Professor, Biostatistics and Medical Informatics Michael N. Gould, Professor, Oncology © Copyright by Keegan D. Korthauer 2015 All Rights Reserved i in memory of my grandparents Ma and Pa FL Grandma and John ii ACKNOWLEDGMENTS First and foremost, I am deeply grateful to my thesis advisor Christina Kendziorski for her invaluable advice, enthusiastic support, and unending patience throughout my time at UW-Madison. She has provided sound wisdom on everything from methodological principles to the intricacies of academic research. I especially appreciate that she has always encouraged me to eke out my own path and I attribute a great deal of credit to her for the successes I have achieved thus far. I also owe special thanks to my committee member Professor Michael Newton, who guided me through one of my first collaborative research experiences and has continued to provide key advice on my thesis research. I am also indebted to the other members of my thesis committee, Professor Sunduz Kele¸s,Professor Sijian Wang, and Professor Michael Gould, whose valuable comments, questions, and suggestions have greatly improved this dissertation.
    [Show full text]
  • Genetic Variation in Pattern-Recognition Receptors and Association with Leprosy 145
    DOI: 10.5772/intechopen.73871 ProvisionalChapter chapter 8 Genetic Variation inin Pattern-RecognitionPattern-Recognition ReceptorsReceptors and and Association withwith LeprosyLeprosy Karina Talita de Oliveira Santana JorgeJorge andand Frederico Marianetti SorianiSoriani Additional information isis available atat thethe endend ofof thethe chapterchapter http://dx.doi.org/10.5772/intechopen.73871 Abstract Mycobacterium leprae is a highly infectious and low pathogenic microorganism that is the causal agent of leprosy. The differences in vulnerability to leprosy, the spectral immune response, and the clinical manifestations of this disease are related to different genetic backgrounds among individuals. In this sense, genetic variants, especially in genes related to mycobacteria recognition and host immune response, may be key factors to explain individual susceptibility and resistance to leprosy and their conditions. In this chapter, studies regarding association of genetic variants in pattern-recognition receptors (PRRs) and leprosy will be reviewed revealing the importance of molecules such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in leprosy initiation and maintenance. Keywords: polymorphisms, pattern-recognition receptors, mycobacterium leprae, leprosy 1. Introduction Leprosy is caused by Mycobacterium leprae, which is an intracellular bacterium with high infectivity and low pathogenicity. It means that there are a large number of people exposed to this pathogen; however, the majority of them are naturally resistant. On the other hand, some people develop leprosy once challenged with M. leprae. The people who develop disease may present different clinical forms of leprosy. Some of them develop a localized disease, named tuberculoid leprosy, with a strong host response, which does not avoid development of nerve injury and physical disabilities.
    [Show full text]
  • Cytotoxic T Cells Class I- Dependent Lymphocyte Killing by NLRC5 Deficiency Selectively Impairs
    The Journal of Immunology NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells Francesco Staehli,* Kristina Ludigs,* Leonhard X. Heinz,† Queralt Seguı´n-Este´vez,‡ Isabel Ferrero,x Marion Braun,x Kate Schroder,{ Manuele Rebsamen,† Aubry Tardivel,* Chantal Mattmann,* H. Robson MacDonald,x Pedro Romero,x Walter Reith,‡ Greta Guarda,*,1 and Ju¨rg Tschopp*,1,2 Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflamma- tory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-kB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5D/D). In this article we show that these animals exhibit slightly decreased CD8+ T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5D/D macrophages efficiently primed CD8+ T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5D/D lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines.
    [Show full text]
  • Inflammasome Activation-Induced Hypercoagulopathy
    cells Review Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients Lealem Gedefaw, Sami Ullah, Polly H. M. Leung , Yin Cai, Shea-Ping Yip * and Chien-Ling Huang * Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China; [email protected] (L.G.); [email protected] (S.U.); [email protected] (P.H.M.L.); [email protected] (Y.C.) * Correspondence: [email protected] (S.-P.Y.); [email protected] (C.-L.H.) Abstract: Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disor- ders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain car- diovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. Citation: Gedefaw, L.; Ullah, S.; Leung, P.H.M.; Cai, Y.; Yip, S.-P.; The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an Huang, C.-L.
    [Show full text]
  • NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival
    JDRXXX10.1177/0022034518775036Journal of Dental ResearchNLRP6 Induces Pyroptosis 775036research-article2018 Research Reports: Biological Journal of Dental Research 2018, Vol. 97(12) 1391 –1398 © International & American Associations NLRP6 Induces Pyroptosis by Activation for Dental Research 2018 Article reuse guidelines: of Caspase-1 in Gingival Fibroblasts sagepub.com/journals-permissions DOI:https://doi.org/10.1177/0022034518775036 10.1177/0022034518775036 journals.sagepub.com/home/jdr W. Liu1* , J. Liu1*, W. Wang1, Y. Wang2,3, and X. Ouyang1 Abstract NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, has been reported to participate in inflammasome formation. Activation of inflammasome triggers a caspase-1–dependent programming cell death called pyroptosis. However, whether NLRP6 induces pyroptosis has not been investigated. In this study, we showed that NLRP6 overexpression activated caspase-1 and gasdermin-D and then induced pyroptosis of human gingival fibroblasts, resulting in release of proinflammatory mediators interleukin (IL)–1β and IL-18. Moreover, NLRP6 was highly expressed in gingival tissue of periodontitis compared with healthy controls. Porphyromonas gingivalis, which is a commensal bacterium and has periodontopathic potential, induced pyroptosis of gingival fibroblasts by activation of NLRP6. Together, we, for the first time, identified that NLRP6 could induce pyroptosis of gingival fibroblasts by activation of caspase-1 and may play a role in periodontitis. Keywords: periodontitis, pattern recognition receptors, cell death, Porphyromonas gingivalis, inflammasomes, flow cytometry Introduction have been demonstrated to participate in periodontitis (Huang et al. 2015; Chaves de Souza et al. 2016; Marchesan et al. Pyroptosis is a newly identified type of programmed cell death 2016).
    [Show full text]
  • Scholarly Commons NLRX1 Modulates Differentially NLRP3
    University of the Pacific Scholarly Commons Dugoni School of Dentistry Faculty Articles Arthur A. Dugoni School of Dentistry 10-1-2018 NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection Shu Chen Hung University of the Pacific Arthur A. Dugoni School of Dentistry Pei Rong Huang Chang Gung University Cassio Luiz Coutinho Almeida-Da-Silva University of the Pacific Arthur A. Dugoni School of Dentistry, [email protected] Kalina R. Atanasova University of Florida Ozlem Yilmaz Medical University of South Carolina See next page for additional authors Follow this and additional works at: https://scholarlycommons.pacific.edu/dugoni-facarticles Part of the Dentistry Commons Recommended Citation Hung, S., Huang, P., Almeida-Da-Silva, C. L., Atanasova, K. R., Yilmaz, O., & Ojcius, D. M. (2018). NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection. Microbes and Infection, 20(9-10), 615–625. DOI: 10.1016/j.micinf.2017.09.014 https://scholarlycommons.pacific.edu/dugoni-facarticles/705 This Article is brought to you for free and open access by the Arthur A. Dugoni School of Dentistry at Scholarly Commons. It has been accepted for inclusion in Dugoni School of Dentistry Faculty Articles by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. Authors Shu Chen Hung, Pei Rong Huang, Cassio Luiz Coutinho Almeida-Da-Silva, Kalina R. Atanasova, Ozlem Yilmaz, and David M. Ojcius This article is available at Scholarly Commons: https://scholarlycommons.pacific.edu/dugoni-facarticles/705 Version of Record: https://www.sciencedirect.com/science/article/pii/S1286457917301582 Manuscript_dd7f93413c97aff4865d54242a8b21e7 1 NLRX1 modulates differentially NLRP3 inflammasome activation 2 and NF-κB signaling during Fusobacterium nucleatum infection 3 4 5 Shu-Chen Hung 1, *, Pei-Rong Huang 2, Cássio Luiz Coutinho Almeida-da-Silva 1,3 , 6 Kalina R.
    [Show full text]
  • The Intestinal Parasite Cryptosporidium Is Controlled by an Enterocyte Intrinsic Inflammasome That Depends on NLRP6
    The intestinal parasite Cryptosporidium is controlled by an enterocyte intrinsic inflammasome that depends on NLRP6 Adam Saterialea,1, Jodi A. Gullicksruda, Julie B. Engilesa, Briana I. McLeoda, Emily M. Kuglera, Jorge Henao-Mejiab,c, Ting Zhoud, Aaron M. Ringd, Igor E. Brodskya, Christopher A. Huntera, and Boris Striepena,2 aDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; bDepartment of Pathology and Laboratory Medicine, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cDivision of Protective Immunity, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; and dDepartment of Immunology, Yale School of Medicine, Yale University, New Haven, CT 06519 Edited by Stephen M. Beverley, Washington University School of Medicine, St. Louis, MO, and approved December 1, 2020 (received for review April 24, 2020) The apicomplexan parasite Cryptosporidium infects the intestinal Murine infection with C. tyzzeri resembles human cryptospo- epithelium. While infection is widespread around the world, chil- ridiosis in location, pathology, and resolution and provides an dren in resource-poor settings suffer a disproportionate disease important tool to define the host and parasite factors that burden. Cryptosporidiosis is a leading cause of diarrheal disease, determine the outcome of infection and to identify the im- responsible for mortality and stunted growth in children. CD4 mune
    [Show full text]
  • Interoperability in Toxicology: Connecting Chemical, Biological, and Complex Disease Data
    INTEROPERABILITY IN TOXICOLOGY: CONNECTING CHEMICAL, BIOLOGICAL, AND COMPLEX DISEASE DATA Sean Mackey Watford A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Gillings School of Global Public Health (Environmental Sciences and Engineering). Chapel Hill 2019 Approved by: Rebecca Fry Matt Martin Avram Gold David Reif Ivan Rusyn © 2019 Sean Mackey Watford ALL RIGHTS RESERVED ii ABSTRACT Sean Mackey Watford: Interoperability in Toxicology: Connecting Chemical, Biological, and Complex Disease Data (Under the direction of Rebecca Fry) The current regulatory framework in toXicology is expanding beyond traditional animal toXicity testing to include new approach methodologies (NAMs) like computational models built using rapidly generated dose-response information like US Environmental Protection Agency’s ToXicity Forecaster (ToXCast) and the interagency collaborative ToX21 initiative. These programs have provided new opportunities for research but also introduced challenges in application of this information to current regulatory needs. One such challenge is linking in vitro chemical bioactivity to adverse outcomes like cancer or other complex diseases. To utilize NAMs in prediction of compleX disease, information from traditional and new sources must be interoperable for easy integration. The work presented here describes the development of a bioinformatic tool, a database of traditional toXicity information with improved interoperability, and efforts to use these new tools together to inform prediction of cancer and complex disease. First, a bioinformatic tool was developed to provide a ranked list of Medical Subject Heading (MeSH) to gene associations based on literature support, enabling connection of compleX diseases to genes potentially involved.
    [Show full text]
  • Post-Transcriptional Inhibition of Luciferase Reporter Assays
    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 34, pp. 28705–28716, August 17, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3* Received for publication, December 12, 2011, and in revised form, June 18, 2012 Published, JBC Papers in Press, June 20, 2012, DOI 10.1074/jbc.M111.333146 Arthur Ling‡1,2, Fraser Soares‡1,2, David O. Croitoru‡1,3, Ivan Tattoli‡§, Leticia A. M. Carneiro‡4, Michele Boniotto¶, Szilvia Benko‡5, Dana J. Philpott§, and Stephen E. Girardin‡6 From the Departments of ‡Laboratory Medicine and Pathobiology and §Immunology, University of Toronto, Toronto M6G 2T6, Canada, and the ¶Modulation of Innate Immune Response, INSERM U1012, Paris South University School of Medicine, 63, rue Gabriel Peri, 94276 Le Kremlin-Bicêtre, France Background: A number of Nod-like receptors (NLRs) have been shown to inhibit signal transduction pathways using luciferase reporter assays (LRAs). Results: Overexpression of NLRX1 and NLRC3 results in nonspecific post-transcriptional inhibition of LRAs. Conclusion: LRAs are not a reliable technique to assess the inhibitory function of NLRs. Downloaded from Significance: The inhibitory role of NLRs on specific signal transduction pathways needs to be reevaluated. Luciferase reporter assays (LRAs) are widely used to assess the Nod-like receptors (NLRs)7 represent an important class of activity of specific signal transduction pathways. Although pow- intracellular pattern recognition molecules (PRMs), which are erful, rapid and convenient, this technique can also generate implicated in the detection and response to microbe- and dan- www.jbc.org artifactual results, as revealed for instance in the case of high ger-associated molecular patterns (MAMPs and DAMPs), throughput screens of inhibitory molecules.
    [Show full text]