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Murine Macrophages Mitochondrial Transcription Factor a in Induction TLR4-Mediated AKT Activation Is MYD88/TRIF-Dependent and Critical for Induction of Oxidative Phosphorylation and Mitochondrial Transcription Factor A in This information is current as Murine Macrophages of September 27, 2021. Christian P. Bauerfeld, Ruchi Rastogi, Gaila Pirockinaite, Icksoo Lee, Maik Hüttemann, Bobby Monks, Morris J. Birnbaum, Luigi Franchi, Gabriel Nuñez and Lobelia Samavati Downloaded from J Immunol published online 6 February 2012 http://www.jimmunol.org/content/early/2012/02/06/jimmun ol.1102157 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/02/06/jimmunol.110215 Material 7.DC1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 6, 2012, doi:10.4049/jimmunol.1102157 The Journal of Immunology TLR4-Mediated AKT Activation Is MYD88/TRIF-Dependent and Critical for Induction of Oxidative Phosphorylation and Mitochondrial Transcription Factor A in Murine Macrophages Christian P. Bauerfeld,*,1 Ruchi Rastogi,† Gaila Pirockinaite,† Icksoo Lee,‡ Maik Hu¨ttemann,‡ Bobby Monks,x Morris J. Birnbaum,x Luigi Franchi,{ Gabriel Nun˜ez,{ and Lobelia Samavati†,‡ Mitochondria play a critical role in cell survival and death. Mitochondrial recovery during inflammatory processes such as sepsis is associated with cell survival. Recovery of cellular respiration, mitochondrial biogenesis, and function requires coordinated expres- Downloaded from sion of transcription factors encoded by nuclear and mitochondrial genes, including mitochondrial transcription factor A (T-fam) and cytochrome c oxidase (COX, complex IV). LPS elicits strong host defenses in mammals with pronounced inflammatory responses, but also triggers activation of survival pathways such as AKT pathway. AKT/PKB is a serine/threonine protein kinase that plays an important role in cell survival, protein synthesis, and controlled inflammation in response to TLRs. Hence we investigated the role of LPS-mediated AKT activation in mitochondrial bioenergetics and function in cultured murine macro- phages (B6-MCL) and bone marrow-derived macrophages. We show that LPS challenge led to increased expression of T-fam and http://www.jimmunol.org/ COX subunits I and IV in a time-dependent manner through early phosphorylation of the PI3K/AKT pathway. PI3K/AKT pathway inhibitors abrogated LPS-mediated T-fam and COX induction. Lack of induction was associated with decreased ATP production, increased proinflammatory cytokines (TNF-a), NO production, and cell death. The TLR4-mediated AKT activation and mitochondrial biogenesis required activation of adaptor protein MYD88 and Toll/IL-1R domain-containing adaptor-inducing IFN-b. Importantly, using a genetic approach, we show that the AKT1 isoform is pivotal in regulating mitochondrial biogenesis in response to TLR4 agonist. The Journal of Immunology, 2012, 188: 000–000. ammalian immune cells evolved to recognize patho- cascade of cellular signaling leading to inflammatory gene ex- by guest on September 27, 2021 gens through pattern recognition receptors, such as pression and clearance of invading organisms. LPS, a major M TLRs that recognize a wide range of microbial path- bacteria-derived cell wall component recognized by TLR4, elicits ogens. Recognition of microbial components by TLRs triggers a strong host defenses in mammals with pronounced inflamma- tory responses (1). Such responses are characterized by activation of inflammatory cascades with release of soluble cytokines and *Department of Pediatrics, St. John Hospital and Medical Center, Detroit, MI 48236; †Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, chemokines such as TNF-a, IL-6, and generation of reactive ox- Wayne State University School of Medicine, Detroit, MI 48201; ‡Center for Molec- ygen species (ROS) and NO that subsequently facilitate the ular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201; xDepartment of Medicine, University of Pennsylvania School of Medicine, eradication of pathogens. Although inflammation is necessary to Philadelphia, PA 19104; and {Department of Pathology, University of Michigan eradicate pathogens, excessive inflammation may lead to host Medical School, Ann Arbor, MI 48109 tissue injury and cell death. This might be, at least in part, because 1Current Address: Division of Critical Care, Department of Pediatrics, University of of the effect of inflammation on mitochondrial bioenergetics and Texas Health Science Center, San Antonio, TX mitochondrial injury. Received for publication July 26, 2011. Accepted for publication January 3, 2012. Mitochondria provide the majority of cellular energy in the form This work was supported by the Department of Medicine, Wayne State University of ATP and are the major source of ROS (2). Cellular immune School of Medicine (L.S.); the Center for Molecular Medicine and Genetics, Wayne State University School of Medicine (L.S., M.H.); and National Institutes of Health response to pathogens requires high energy in the form of ATP, Grants R01 DK61707 (to G.N.) and R01 DK56886 (to M.J.B.). and it appears that TLR-mediated mitochondrial ROS (mROS) are Address correspondence and reprint requests to Dr. Lobelia Samavati, Division of important for macrophage bactericidal activity (3). However, ex- Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Wayne State cessive reactive oxygen and nitrogen species generation during University School of Medicine, 3 Hudson, 3990 John R Street, Detroit, MI 48201. E-mail address: [email protected] inflammation may damage mitochondria, causing bioenergetic The online version of this article contains supplemental material. failure. This process is thought to be due to inhibition of the electron transfer chain (ETC) (4) through secondary modification Abbreviations used in this article: BMDM, bone marrow-derived macrophage; COX, cytochrome c oxidase; ETC, electron transfer chain; FCCP, carbonyl cyanide 4-(tri- of enzymes involved in oxidative phosphorylation (OxPhos) and fluoromethoxy) phenylhydrazone; MnSOD, manganese superoxide dismutase; uncoupling of electron transport from ATP synthesis. Using an mROS, mitochondrial reactive oxygen species; NRF-1, nuclear respiratory factor 1; OxPhos, oxidative phosphorylation; PGC-1a, peroxisome proliferator-activated inflammation model, we have shown that TNF-a inhibits the ac- receptor g coactivator-1-a; ROS, reactive oxygen species; T-fam, mitochondrial tivity of cytochrome c oxidase (COX) in bovine liver and in transcription factor A; TMRM, tetramethylrhodamine-methylester; TRIF, Toll/IL- murine hepatocytes (5). This inhibition was associated with de- 1R domain-containing adapter-inducing IFN-b; WT, wild-type. creased ATP production and defective electron transport to mo- Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 lecular oxygen. Several reports suggest regeneration of mitochon- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102157 2 LPS AND MITOCHONDRIAL BIOENERGETICS dria, upregulation of ETC capacity, and generation of new mito- (Ipswich, MA). Anti-mouse IgG and anti-rabbit IgG HRP-linked Abs were chondria later in the disease process after acute insults such as purchased from Cell Signaling Technology (Beverly, CA), and anti-goat hypoxemia or sepsis are important for survival (6–8). The exact HRP was purchased from Bio-Rad (Hercules, CA). mechanism underlying the recovery of bioenergetic failure after Cell culture inflammatory insult is not well studied. 2 2 The mouse macrophage cell line (B6-MCL) and MYD88/TRIF / cell line LPS stimulation under specific conditions leads to activation of were generous gifts of Dr. Eicke Latz (University of Massachusetts the prosurvival cascade followed by growth and differentiation. For Medical School, Worcester, MA). Both cell lines were generated from example, it has been shown that LPS may serve as a signal to wild-type (WT) C57BL6 mice as previously described (19), and MYD88/ 2/2 promote preconditioning and to protect against reperfusion in- TRIF macrophages were generated from the same background mice as previously described (20). B6-MCL and cells deficient in MYD88/TRIF jury (9). This bifunctionality of LPS is neither well understood were grown in IMDM supplemented with 10% heat-inactivated FCS, nor studied. Among numerous pathways activated through TLR- antibiotics, sodium pyruvate, nonessential amino acids, and 2-ME. mediated signaling, the PI3K/AKT pathway plays a central role in RAW 264.7 cells were obtained from American Type Culture Collection the regulation of cell survival and proliferation (9, 10). Evidence (Manassas, VA). Cells were maintained in a 95% air, 5% CO2 humidified suggests an important
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