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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
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