Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation

• Published in: PLoS pathogens Vol. 16; no. 10; p. e1008929
• Main Authors: Genoula, Melanie, Marín Franco, José Luis, Maio, Mariano, Dolotowicz, Belén, Ferreyra, Malena, Milillo, M. Ayelén, Mascarau, Rémi, Moraña, Eduardo José, Palmero, Domingo, Matteo, Mario, Fuentes, Federico, López, Beatriz, Barrionuevo, Paula, Neyrolles, Olivier, Cougoule, Céline, Lugo-Villarino, Geanncarlo, Vérollet, Christel, Sasiain, María del Carmen, Balboa, Luciana
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2020; Public Library of Science (PLoS)
• Subjects: Adaptive immunology; Animals; Bacteriology; Biology and Life Sciences; Bone marrow; Cell activation; Fatty acids; Foam Cells - microbiology; Funding; Glycolysis; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunology; Infections; Innate immunity; Interleukin 4; Laboratories; Life Sciences; Lipid bodies; Lipid Droplets - metabolism; Lipid Metabolism; Lipids; Lipolysis; Macrophage Activation - physiology; Macrophages; Macrophages - metabolism; Macrophages - microbiology; Male; Medicine and Health Sciences; Metabolic pathways; Metabolism; Mice, Inbred BALB C; Microbiology and Parasitology; Mitochondria; Mycobacterium tuberculosis; Mycobacterium tuberculosis - pathogenicity; Mycobacterium tuberculosis - physiology; Oxidation; Pathogens; Phosphorylation; Physical Sciences; Pleural effusion; Research and Analysis Methods; Software; Stat6 protein; Transcription; Tuberculosis; Tuberculosis - microbiology; France; Argentina
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008929

The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies.