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      Targeting Evolutionary Conserved Oxidative Stress and Immunometabolic Pathways for the Treatment of Respiratory Infectious Diseases

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          Abstract

          Significance: Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease, as well as cancer.

          Recent Advances: There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilizes endogenous ROS production via NADPH oxidase (NOX)2-containing NOXs and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilization of hypoxia-inducible factor-1α, promoting interleukin-1β production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle.

          Critical Issues: The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as Streptococcus pneumoniae.

          Future Directions: Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.

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          Most cited references137

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          TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

          Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria, and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase (Phox) machinery 1 . However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to macrophage bactericidal activity, although the mechanisms linking innate immune signaling to mitochondria for mROS generation remain unclear 2-4 . Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of the TLR signaling adapter tumor necrosis factor receptor-associated factor 6 (TRAF6) to mitochondria where it engages evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a protein implicated in mitochondrial respiratory chain assembly 5 . Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT and TRAF6 depleted macrophages exhibit decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results therefore reveal a novel pathway linking innate immune signaling to mitochondria, implicate mROS as important components of antibacterial responses, and further establish mitochondria as hubs for innate immune signaling.
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            Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

            Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
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              Missing pieces in the NF-kappaB puzzle.

              The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.
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                Author and article information

                Journal
                Antioxid Redox Signal
                Antioxid. Redox Signal
                ars
                Antioxidants & Redox Signaling
                Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                1523-0864
                1557-7716
                May 1, 202
                24 March 2020
                24 March 2020
                : 32
                : 13
                : 993-1013
                Affiliations
                [ 1 ]Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Australia.
                [ 2 ]School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, Australia.
                [ 3 ]Department of Histopathology, Trinity College Dublin, Dublin, Ireland.
                [ 4 ]Sir Patrick Dun's Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin, Ireland.
                [ 5 ]Molecular Pathology Laboratory, Coombe Women and Infants' University Hospital, Dublin, Ireland.
                Author notes
                [*]

                These two authors had equal contribution.

                [*]Address correspondence to: Prof. Stavros Selemidis, Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, VIC 3083, Australia stavros.selemidis@ 123456rmit.edu.au
                Article
                10.1089/ars.2020.8028
                10.1089/ars.2020.8028
                7426980
                32008371
                283b0bf5-ad83-4dcf-a74e-246e1d5d9a3a
                © Jonathan R. Erlich et al., 2020; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : Date of first submission to ARS Central, January 12, 2020
                : date of acceptance, January 18, 2020
                Page count
                Figures: 4, Tables: 2, References: 190, Pages: 21
                Categories
                Forum Review Articles

                metabolism,nadph oxidase,mitochondria,influenza,immunity,co-infection

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