title: The Warburg effect in mycobacterial granulomas is dependent on the recruitment and activation of macrophages by interferon-γ.
abstract: Granulomas are the hallmark of mycobacterial disease. Here, we demonstrate that both the cell recruitment and the increased glucose consumption in granulomatous infiltrates during Mycobacterium avium infection are highly dependent on interferon-γ (IFN-γ). Mycobacterium avium-infected mice lacking IFN-γ signalling failed to developed significant inflammatory infiltrations and lacked the characteristic uptake of the glucose analogue fluorine-18-fluorodeoxyglucose (FDG). To assess the role of macrophages in glucose uptake we infected mice with a selective impairment of IFN-γ signalling in the macrophage lineage (MIIG mice). Although only a partial reduction of the granulomatous areas was observed in infected MIIG mice, the insensitivity of macrophages to IFN-γ reduced the accumulation of FDG. In vivo, ex vivo and in vitro assays showed that macrophage activated by IFN-γ displayed increased rates of glucose uptake and in vitro studies showed also that they had increased lactate production and increased expression of key glycolytic enzymes. Overall, our results show that the activation of macrophages by IFN-γ is responsible for the Warburg effect observed in organs infected with M. avium.
authors: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors: Rui
authors: R
authors: Appelberg
authors: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.|Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors: Diana
authors: D
authors: Moreira
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Palmira
authors: P
authors: Barreira-Silva
authors: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.|Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors: Margarida
authors: M
authors: Borges
authors: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors: Letícia
authors: L
authors: Silva
authors: Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Sciences, IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Advanced Institute of Health Sciences - North (ISCS-N), CESPU, CRL, Gandra, Portugal.|UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors: Ricardo Jorge
authors: RJ
authors: Dinis-Oliveira
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Mariana
authors: M
authors: Resende
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Margarida
authors: M
authors: Correia-Neves
authors: Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Michael B
authors: MB
authors: Jordan
authors: Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors: Nuno C
authors: NC
authors: Ferreira
authors: Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors: Antero J
authors: AJ
authors: Abrunhosa
authors: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.|Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Ricardo
authors: R
authors: Silvestre
mesh_terms: D000818:Animals; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000662:veterinary; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D019344:Lactic Acid / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009162:Mycobacterium avium / Q000276:immunology*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000494:pharmacology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000662:veterinary
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D019344:Lactic Acid; D007371:Interferon-gamma
keywords: glycolysis; infection; interferon-γ; macrophages; mycobacteria