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      The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition

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          Abstract

          Mycobacterium tuberculosis is a facultative anaerobe and its characteristic pathological hallmark, the granuloma, exhibits hypoxia in humans and in most experimental models. Thus the host and bacillary adaptation to hypoxia is of central importance in understanding pathogenesis and thereby to derive new drug treatments and vaccines.

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          Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.

          Divya Vats, Lata Mukundan, Justin Odegaard … (2006)
          Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.
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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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              HIF-1alpha is essential for myeloid cell-mediated inflammation.

              Thorsten Cramer, Yuji Yamanishi, Björn E Clausen … (2003)
              Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.
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                Author and article information

                Contributors
                Robert J. Wilkinson
                Journal
                Journal ID (nlm-ta): Microbes Infect
                Journal ID (iso-abbrev): Microbes Infect
                Title: Microbes and Infection
                Publisher: Elsevier
                ISSN (Print): 1286-4579
                ISSN (Electronic): 1769-714X
                Publication date PMC-release: 1 March 2017
                Publication date (Print): March 2017
                Volume: 19
                Issue: 3
                Pages: 177-192
                Affiliations
                [a ]Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, 20892, United States
                [b ]Microbial Interface Biology, Priority Research Area Infections, Forschungszentrum Borstel, Leibniz Center for Medicine and Biosciences, Parkallee 1-40, D-23845, Borstel, Germany
                [c ]Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa
                [d ]The Francis Crick Institute, London, NW1 2AT, United Kingdom
                [e ]Department of Medicine, Imperial College, London, W2 1PG, United Kingdom
                [f ]German Center for Infection Research (DZIF), Partner Site Hamburg-Borstel-Lübeck, Borstel, Germany
                Author notes
                [∗ ]Corresponding author. University of Cape Town, South Africa. Fax: +27 21 406 6796.University of Cape TownSouth Africa r.j.wilkinson@ 123456imperial.ac.uk
                [1]

                These authors contributed equally to the manuscript.

                Article
                Publisher ID: S1286-4579(16)30146-0
                DOI: 10.1016/j.micinf.2016.10.001
                PMC ID: 5335906
                PubMed ID: 27780773
                SO-VID: 44211a93-fb50-49b4-8bcd-33d8dfc09297
                Copyright © © 2016 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 8 September 2016
                Date accepted : 6 October 2016
                Categories
                Subject: Article

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: tuberculosis,hypoxia,t cells,antigens,macrophage,lipid droplets
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: tuberculosis, hypoxia, t cells, antigens, macrophage, lipid droplets

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