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Peroxiredoxin 1 Contributes to Host Defenses Against Mycobacterium Peroxiredoxin 1 Contributes to Host Defenses against Mycobacterium tuberculosis Kazunori Matsumura, Hiroki Iwai, Masako Kato-Miyazawa, Fumiko Kirikae, Jizi Zhao, Toru Yanagawa, Tetsuro Ishii, This information is current as Tohru Miyoshi-Akiyama, Keiji Funatogawa and Teruo of September 27, 2021. Kirikae J Immunol published online 7 September 2016 http://www.jimmunol.org/content/early/2016/09/07/jimmun ol.1601010 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/09/07/jimmunol.160101 Material 0.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 27, 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 September 7, 2016, doi:10.4049/jimmunol.1601010 The Journal of Immunology Peroxiredoxin 1 Contributes to Host Defenses against Mycobacterium tuberculosis Kazunori Matsumura,* Hiroki Iwai,* Masako Kato-Miyazawa,* Fumiko Kirikae,* Jizi Zhao,* Toru Yanagawa,† Tetsuro Ishii,† Tohru Miyoshi-Akiyama,* Keiji Funatogawa,‡ and Teruo Kirikae* Peroxiredoxin (PRDX)1 is an antioxidant that detoxifies hydrogen peroxide and peroxinitrite. Compared with wild-type (WT) mice, Prdx1-deficient (Prdx12/2) mice showed increased susceptibility to Mycobacterium tuberculosis and lower levels of IFN-g and IFN- g–producing CD4+ T cells in the lungs after M. tuberculosis infection. IL-12 production, c-Rel induction, and p38 MAPK activation levels were lower in Prdx12/2 than in WT bone marrow–derived macrophages (BMDMs). IFN-g–activated Prdx12/2 BMDMs did not kill M. tubercuosis effectively. NO production levels were lower, and arginase activity and arginase 1 (Arg1) expression levels were higher, in IFN-g–activated Prdx12/2 than in WT BMDMs after M. tuberculosis infection. An arginase Downloaded from inhibitor, Nv-hydroxy-nor-arginine, restored antimicrobial activity and NO production in IFN-g–activated Prdx12/2 BMDMs after M. tuberculosis infection. These results suggest that PRDX1 contributes to host defenses against M. tuberculosis. PRDX1 positively regulates IL-12 production by inducing c-Rel and activating p38 MAPK, and it positively regulates NO production by suppressing Arg1 expression in macrophages infected with M. tuberculosis. The Journal of Immunology, 2016, 197: 000–000. ycobacterium tuberculosis, a causative agent of tuber- cannot inhibit the intracellular growth of M. tuberculosis as ef- http://www.jimmunol.org/ culosis (TB), is responsible for ∼9 million new cases of fectively as do WT Mfs (7). In contrast, the roles of ROS in host M active TB and 1.5 million deaths per year (1). Th1 re- defenses against M. tuberculosis are unclear. NADPH oxidase is sponses play a central role in host defenses against M. tuberculosis composed of five polypeptide subunits, gp91-phox, p22-phox, (2). Following M. tuberculosis infection, macrophages (Mfs) and p40-phox, p47-phox, and p67-phox, encoded by Cybb, Cyba, dendritic cells (DCs) produce inflammatory cytokines such as Ncf4, Nrf1, and Ncf2, respectively, which bind to the Rac1 and IL-1, IL-6, IL-12, and TNF-a, with IL-12 being essential for the Rac2 GTPases, encoded by Rac1 and Rac2, respectively (8). One 2/2 differentiation of CD4+ T cells into Th1 cells (3). Th1 cells release study reported that Cybb mice were more susceptible to IFN-g, which activates the antimicrobial activities of Mfs. These M. tuberculosis than WT mice (5), whereas another study reported by guest on September 27, 2021 2/2 activated Mfs produce reactive nitrogen species (RNS) and re- no difference in susceptibility (9). Nrf1 mice showed increased active oxygen species (ROS) via the enzymes NO synthase (NOS) M. tuberculosis growth during the early period of infection (10). Moreover, compared with WT Mfs, IFN-g–activated Cybb2/2 2 and reduced NADPH oxidase, respectively (4). 2/2 RNS play a critical role in host defenses against M. tuberculosis. and Nrf1 Mfs similarly inhibited the intracellular growth of NOS2-deficient (Nos22/2) mice are more susceptible to M. tuberculosis M. tuberculosis (5, 7). These findings were likely due to the ability 2/2 M. tuberculosis than are wild-type (WT) mice (5, 6), and MfsfromNos2 mice of to produce ROS scavenging enzymes (11). Alteration of RNS metabolism affects susceptibility to M. tuberculosis (12). L-Arginine is converted by NOS2 to NO and *Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan; †Faculty of Medicine, Uni- L-citrulline or by ARG1 to urea and L-ornithine (13). ARG1, versity of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; and ‡Department of Micro- therefore, competes with NOS2 for the same substrate, reducing NO biology, Tochigi Prefectural Institute of Public Health and Environmental Science, production by activated Mfs (14). Compared with WT mice, mice Utsunomiya, Tochigi 329-1196, Japan lacking Mf ARG1 showed decreased numbers of M. tuberculosis ORCID: 0000-0001-8807-3957 (H.I.). and increased NO in the lungs after M. tuberculosis infection (12). Received for publication June 10, 2016. Accepted for publication August 16, 2016. It is unclear whether alteration of ROS metabolism affects This work was supported by National Center for Global Health and Medicine Grants susceptibility to M. tuberculosis. Peroxiredoxin (PRDX)1, a major 21-A-105, 24-A-103, and 27-A-1102, Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research 22590411, and by Japan Agency for Medical cytosolic PRDX, is expressed ubiquitously in tissues and affects Research and Development Grant 16fk0108302h0003. ROS metabolism (15, 16). PRDXs are a mammalian family of Address correspondence and reprint requests to Dr. Teruo Kirikae, Department of antioxidants that reduce hydrogen peroxide, organic hydroperox- Infectious Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan. E-mail address: ides, and peroxinitrite, protecting cells and tissues from oxidative [email protected] and nitrosative stresses (15, 16). PRDX1 has protective effects on The online version of this article contains supplemental material. oxidative injury induced by Helicobacter pylori (17), kidney Abbreviations used in this article: ASK1, apoptosis signal–regulating kinase 1; damage by administration of ferric nitrilotriacetate (18), and BMDM, bone marrow–derived Mf; 9-cRA, 9-cis retinoic acid; DC, dendritic cell; pulmonary inflammation induced by bleomycin administration Mf, macrophage; MKK, MAPK kinase; MOI, multiplicity of infection; nor-NOHA, v (19), suggesting that protective effects of PRDX1 depend on its N -hydroxy-nor-L-arginine; NOS, NO synthase; PFA, paraformaldehyde; p.i., post- infection; PRDX, peroxiredoxin; PTEN, phosphatase and tensin homolog; qRT-PCR, radical scavenger activity. quantitative RT-PCR; RNS, reactive nitrogen species; ROS, reactive oxygen species; It is known that PRDX1 has functions other than the radical SOCS, suppressor of cytokine signaling; TB, tuberculosis; WT, wild-type. scavenger activity. PRDX1 serves as chaperone in the form of Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 oligomer (16, 20). PRDX1 regulates innate immune responses www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601010 2 PRDX1 CONTRIBUTES TO HOST DEFENSES AGAINST TB necessary for restoration of damaged tissue. PRDX1 increases bright-field images using Photoshop CS 11 (Adobe Systems, San Jose, CA). acute pulmonary inflammation due to O3 exposure (21). In the case of brain stroke, which causes ischemia–reperfusion injury, Cytokine/chemokine measurements PRDX1 released from necrotic cells worsened the brain damage via initiating inflammation (22). Recombinant PRDX1 binds Cytokine/chemokine levels in organs were measured using Milliplex MAP mouse cytokine/chemokine premixed 22-plex kits (Merck, Kenilworth, NJ) TLR4 and positively regulates inflammation (22–24). and a Luminex 200 (Luminex, Austin, TX), according to the manufacturers’ We hypothesized that loss of PRDX1 would increase resistance instructions. The kits detect G-CSF, GM-CSF, IFN-g, IL-1a, IL-1b, sIL-2, to M. tuberculosis. Prdx12/2 Mfs will contain excess RNS and IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 p70, IL-13, IL-15, IL-17, TNF-a, ROS, inhibiting the intracellular growth of M. tuberculosis.ROS CCL2, CCL3, CCL5, CXCL1, and CXCL10. Cytokine concentrations in cell culture supernatants were measured using ELISA kits (R&D Systems, activate NF-kB (25), leading to increased production of inflammatory Minneapolis, MN), according to the manufacturer’s instructions. cytokines by Prdx12/2 relative to WT MfsduringM. tuberculosis infection. Unexpectedly, we found that Prdx12/2 mice were more Flow cytometric analysis susceptible to M. tuberculosis than were
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