부산대학교 도서관

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. Author summary: Tuberculosis is a deadly disease caused by Mycobacterium tuberculosis. Although progress has been made in tuberculosis control, there are unexplored aspects of how the immune system deals with the pathogen that need to be addressed. M. tuberculosis primarily lives in macrophages, immune cells which can destroy mycobacteria. In spite of the multiple microbicidal properties, the bacterium still manipulates the metabolism of macrophages, reflected in the accumulation lipid droplets and consequent differentiation into foamy macrophages. These lipid-laden macrophages constitute a favorable niche for the bacteria to persist hidden from our immune defense. Macrophages are classified into different programs depending on how they are activated by environmental signals, ranging from classically (microbicidal/inflammatory) to alternatively (tissue remodeling/repair/growth) activated spectrum extremes. We found that, unlike other programs, alternatively activated macrophages are reluctant to accumulate lipid droplets due to the signal transducer and activator of transcription 6 (STAT6), which promotes the degradation of those lipids. Notwithstanding, M. tuberculosis counteracts lipolysis by rewiring the metabolism of alternatively activated macrophages towards the accumulation of lipid droplets via the activation of the hypoxia-inducible factor 1-alpha (HIF-1α). Therefore, this study contributes to the better understanding of how bacillus shifts the metabolism of macrophages, which can be crucial to therapeutic purposes. [ABSTRACT FROM AUTHOR]