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Nrf2 Modulates Host Defense During Streptococcus Pneumoniae Pneumonia in Mice

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Nrf2 Modulates Host Defense During Streptococcus Pneumoniae Pneumonia in Mice Nrf2 Modulates Host Defense during Streptococcus pneumoniae Pneumonia in Mice This information is current as John C. Gomez, Hong Dang, Jessica R. Martin and Claire of September 28, 2021. M. Doerschuk J Immunol published online 26 August 2016 http://www.jimmunol.org/content/early/2016/08/26/jimmun ol.1600043 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/08/26/jimmunol.160004 Material 3.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 26, 2016, doi:10.4049/jimmunol.1600043 The Journal of Immunology Nrf2 Modulates Host Defense during Streptococcus pneumoniae Pneumonia in Mice John C. Gomez,*,† Hong Dang,†,‡ Jessica R. Martin,*,† and Claire M. Doerschuk*,†,x Nrf2 regulates the transcriptional response to oxidative stress. These studies tested the role of Nrf2 during Streptococcus pneumoniae pneumonia and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils. Nrf2 null and wild type (WT) mice were studied at 6 and 24 h after instillation of S. pneumoniae or PBS. At 6 h, fewer neutrophils were recruited and the number of bacteria remaining in the lungs tended to be less (p = 0.06) in the Nrf2 null compared with WT mice. In uninfected lungs, 53 genes were already differentially expressed in Nrf2 null compared with WT mouse lungs, and gene sets involved in phagocytosis, Fc receptor function, complement, and Ig regulation are enhanced in PBS-treated Nrf2 null gene profiles compared with those of WT mice. These results suggest that initial host defense is enhanced in Nrf2 null mice, resulting in less recruitment of neutrophils. At 24 h, neutrophil recruitment was greater. The percentages of early apoptotic and late apoptotic/necrotic neutrophils were similar. At Downloaded from increasing inoculum numbers, mortality rates strikingly increased from 15 to 31 and 100% in Nrf2 null mice, whereas all WT mice survived, and Nrf2 null mice had a defect in clearance, particularly at the intermediate dose. The mortality was due to enhanced lung injury and greater systemic response. Gene profiling identified differentially regulated genes and pathways in neutrophils and lung tissue, including those involved in redox stress response, metabolism, inflammation, immunoregulatory pathways, and tissue repair, providing insight into the mechanisms for the greater tissue damage and increased neutrophil accumulation. The Journal of Immunology, 2016, 197: 000–000. http://www.jimmunol.org/ he transcription factor Nrf2 (NF erythroid-derived 2-like 2 target in diseases in which oxidative stress contributes to patho- [Nfe2l2]) is a critical regulator of the cellular response to genesis, such as cancer, multiple sclerosis, and chronic obstructive T oxidative stress. At baseline, Nrf2 is kept in the cytoplasm pulmonary disease (COPD) (2). by its inhibitor Keap1 and very rapidly targeted for proteasomal Nrf2 plays a critical protective role in the lungs, which are con- degradation, with a half-life of ∼15 min (1). Upon exposure to tinually exposed to oxidative stress because of inhaled oxidants. oxidative stress, Nrf2 translocates to the nucleus, where it binds to Numerous studies using Nrf2-deficient mice have demonstrated the antioxidant response elements (AREs) in the promoter region of role of Nrf2 in mouse models of lung carcinogenesis, viral infections, allergy and asthma, pulmonary fibrosis, COPD, and acute lung injury by guest on September 28, 2021 target genes to activate transcription of detoxifying and antioxidant (3). Previous work has also shown that Nrf2 may play an important enzymes and other cytoprotective pathways (2). Nrf2 activation thus role in inflammation and the innate immune response to bacterial restores intracellular redox balance, preventing oxidative damage to pathogens in the lungs. In response to LPS instillation into the lungs, the cell. Nrf2 has garnered wide attention as a potential therapeutic Nrf2-deficient mice showed increased neutrophil recruitment, greater TNF levels, and increased NF-kBactivationcomparedwithwildtype *Center for Airways Disease, University of North Carolina at Chapel Hill, Chapel (WT) mice (4, 5). Deficiency of Nrf2 leads to increased lung injury Hill, NC 27599; †Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; ‡Cystic Fibrosis/Pulmonary Research and Treatment associated with defects in mitochondrial biogenesis and mitophagy in Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and alveolar type 2 cells, as well as greater expression of the genes x Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, encoding the inflammatory cytokines IL-1, TNF, and CCL2 (MCP-1) NC 27599 and lower expression of the anti-inflammatory cytokine IL-10 com- ORCID: 0000-0002-1145-2235 (J.R.M.). pared with WT mice during Staphylococcus aureus–induced pneu- Received for publication January 8, 2016. Accepted for publication July 28, 2016. monia and sepsis (6, 7). Activating Nrf2 improved bacterial clearance This work was supported by National Institutes of Health Grants HL 048160, HL from the lungs in mice exposed to cigarette smoke, and sulforaphane 052466, HL 114388, T32 HL007106, UH2HL 123645, and P30 CA016086 to the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center. The treatment of alveolar macrophages from COPD patients improved UNC Flow Cytometry Core Facility is supported by Cancer Center Core Support their ability to phagocytose bacteria, at least in part, through Nrf2 Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center. activation (8). Nrf2 null mice showedincreasedinflammation, injury, The microarray data presented in this article have been deposited into the Gene and bacterial load during pulmonary infection with P. aeruginosa Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under series GSE83615. after hyperoxia (9). Our initial studies demonstrated that neutrophils Address correspondence and reprint requests to Dr. Claire M. Doerschuk, 7205 Marsico Hall, CB #7248, University of North Carolina, Chapel Hill, NC 27599- express Nrf2 (10), but its functional significance in regulating gene 7248. E-mail address: [email protected] transcription within these cells has not been evaluated. The online version of this article contains supplemental material. These studies tested the hypothesis that Nrf2 regulates lung host Abbreviations used in this article: ARE, antioxidant response element; BAL, defense during bacterial pneumonia induced by Streptococcus bronchoalveolar lavage; BALF, BAL fluid; COPD, chronic obstructive pulmonary pneumoniae, the most common cause of community-acquired disease; DAMP, damage-associated molecular pattern; DE, differentially expressed; DEG, DE gene; FDR, false discovery rate; GO, Gene Ontology; GSEA, Gene Set pneumonia. Host defense and the inflammatory response were 2/2 Enrichment Analysis; Nfe2l2, NF erythroid-derived 2-like 2; sICAM-1, soluble examined in Nrf2 null (Nfe2l2 ) and WT mice given either PBS ICAM-1; TBARS, thiobarbituric acid reactive substances; UNC, University of North (uninfected) or S. pneumoniae for 6 or 24 h. Gene profiling was Carolina; WT, wild type. performed in both the whole lung tissue and the lung neutrophils Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 isolated from the PBS- or S. pneumoniae–treated lungs. We www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600043 2 Nrf2 REGULATES HOST RESPONSE DURING S. PNEUMONIAE PNEUMONIA determined the role of Nrf2 in neutrophils recruited to the lungs and clearance. Unless specified otherwise, the range of CFU instilled was 0.57– 8 identified pathways and potential mechanisms through which Nrf2 1.7 3 10 CFU/ml instillate. modulates the inflammatory response and subsequent resolution and In bacterial clearance studies where mice received intermediate or high doses of S. pneumoniae, surviving mice were euthanized after 18 h. Blood tissue repair. was obtained through the inferior vena cava and lungs and spleens were dissected aseptically. Lungs and spleens were homogenized in sterile PBS. Materials and Methods Aliquots of blood and lung and spleen homogenates were plated on agar plates, and CFU were counted as described earlier. The number of CFU per Mice milliliter of instillate was 0.57–1.7 3 108 (low dose), 5.4 3 108 (inter- 3 9 Adult C57BL/6 (WT) mice were purchased from Jackson Laboratory (Bar mediate dose), and 2.5 10 (high dose). The volume of instillate given Harbor, ME). Mice deficient in Nrf2 (Nfe2l22/2) were kindly provided by was adjusted for body weight (2.3 ml/g body weight), and the number of Dr. Masayuki Yamamoto at
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