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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 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 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: 2864–2879. 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 target genes to activate transcription of detoxifying and antioxidant (3). Previous work has also shown thatNrf2mayplayanimportant 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-kB activation compared with wild type *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 showed increased inflammation, 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 The Journal of Immunology 2865 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 Tohoku University (11), and a colony was CFU given per mouse is calculated for each experiment. developed. Mice were bred and housed side by side in ventilated racks Screening assays for oxidative stress and antioxidant capacity within a specific pathogen-free facility. Age- and sex-matched mice were used at 6–12 wk of age. All animal studies were performed in compliance Measurement of thiobarbituric acid reactive substances (TBARS) and with the U.S. Department of Health and Human Services Guide for the antioxidant capacity was performed using assay kits from Cayman Care and Use of Laboratory Animals. Animal studies were reviewed and Chemical (Ann Arbor, MI), and assays were performed according to the approved by our Institutional Animal Care and Use Committee. manufacturer’s instructions. In brief, pneumonic lungs were homogenized in PBS, and the homogenates were centrifuged at 1600 3 g for 10 min at Bacterial pneumonia 4˚C. An aliquot of the resulting supernatant was obtained for measurement S. pneumoniae (serotype 19; ATCC 49619) was purchased from American of antioxidant capacity. An equal volume of radioimmunoprecipitation Type Culture Collection (Manassas, VA). S. pneumoniae was grown at 37˚C assay buffer was then added to the remaining homogenate, the sample was spun, and TBARS were measured in the supernatant. All samples were with 5% CO2 on trypticase soy agar containing 5% defibrinated sheep 2 blood. Suspensions of S. pneumoniae were prepared in PBS, and bacterial stored at 80˚C before performing the assays. dose was estimated based on the absorbance of the bacterial suspension at 600 nm. Pneumonia was induced by intratracheal instillation of the pre- Quantifying damage-associated molecular patterns and other pared bacterial suspension into the left lung (2.3 ml of the bacterial sus- markers of alveolar injury in the BALF pension per gram mouse body weight). The number of bacterial CFU At 6 or 24 h after instillation of S. pneumoniae (5.8–15 3 106 CFU/mouse) instilled was quantified by plating serial dilutions of the bacterial sus- in Nrf2 null and WT mice, the pulmonary vasculature was flushed with pension on agar plates, as in the lungs and spleens (see later).
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