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      Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

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          Abstract

          Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems.

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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.

          Eva M. Pålsson-McDermott, Anne M Curtis, Gautam Goel … (2015)
          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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            Synchronized renal tubular cell death involves ferroptosis.

            Andreas Linkermann, Rachid Skouta, Nina Himmerkus … (2014)
            Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.
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              TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation.

              Bart Everts, Eyal Amiel, Stanley Ching-Cheng Huang … (2014)
              The ligation of Toll-like receptors (TLRs) leads to rapid activation of dendritic cells (DCs). However, the metabolic requirements that support this process remain poorly defined. We found that DC glycolytic flux increased within minutes of exposure to TLR agonists and that this served an essential role in supporting the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi required for the production and secretion of proteins that are integral to DC activation. Signaling via the kinases TBK1, IKKɛ and Akt was essential for the TLR-induced increase in glycolysis by promoting the association of the glycolytic enzyme HK-II with mitochondria. In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs.
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                Author and article information

                Contributors
                Claude Libert:
                ORCID: http://orcid.org/0000-0001-6408-036X
                claude.libert@IRC.VIB-UGent.be
                Journal
                Journal ID (nlm-ta): EMBO Mol Med
                Journal ID (iso-abbrev): EMBO Mol Med
                Journal ID (doi): 10.1002/(ISSN)1757-4684
                Journal ID (publisher-id): EMMM
                Journal ID (hwp): embomm
                Title: EMBO Molecular Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1757-4676
                ISSN (Electronic): 1757-4684
                Publication date (Electronic): 05 July 2018
                Publication date (Print): August 2018
                Volume: 10
                Issue: 8 ( doiID: 10.1002/emmm.v10.8 )
                Electronic Location Identifier: e8712
                Affiliations
                [ 1 ] Center for Inflammation Research VIB Ghent Belgium
                [ 2 ] Department of Biomedical Molecular Biology Ghent University Ghent Belgium
                Author notes
                [*] [* ]Corresponding author. Tel: +32 93313700; E‐mail: claude.libert@ 123456IRC.VIB-UGent.be
                [†]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-9078-0113
                http://orcid.org/0000-0003-1844-6476
                http://orcid.org/0000-0001-6408-036X
                Article
                Publisher ID: EMMM201708712
                DOI: 10.15252/emmm.201708712
                PMC ID: 6079534
                PubMed ID: 29976786
                SO-VID: dba0e1d8-278e-49ec-be76-d0ebb96998f9
                Copyright © © 2018 The Authors. Published under the terms of the CC BY 4.0 license
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 22 November 2017
                Date revision received : 27 April 2018
                Date accepted : 25 May 2018
                Page count
                Figures: 6, Tables: 0, Pages: 18, Words: 16802
                Funding
                Funded by: Agency for Innovation of Science and Technology in Flanders (IWT)
                Funded by: Research Council of Ghent University (GOA Program)
                Funded by: Research Foundation Flanders (FWO Vlaanderen)
                Funded by: COST Action
                Award ID: BM1402
                Funded by: Interuniversity Attraction Poles Program of the Belgian Science Policy
                Award ID: IAP‐VI‐18
                Categories
                Subject: Review
                Subject: Review
                Custom metadata
                source-schema-version-number 2.0
                component-id emmm201708712
                cover-date August 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:07.08.2018

                ScienceOpen disciplines: Molecular medicine
                Keywords: hypoxia,inflammation,interventions,metabolic reprogramming,sepsis,immunology,metabolism,microbiology, virology & host pathogen interaction
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: hypoxia, inflammation, interventions, metabolic reprogramming, sepsis, immunology, metabolism, microbiology, virology & host pathogen interaction

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