IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
THE PLEURAL EFFUSIONS FROM TB PATIENTS ALTER THE METABOLIC REPROGRAMMING OF HUMAN MACROPHAGES BY TARGETING HIF-1A ACTIVITY
Autor/es:
JOSE LUIS MARIN FRANCO; DUETTE, GABRIEL; FERREYRA, MALENA; DOMINGO PALMERO; PABLO SCHIERLOH; BALBOA, LUCIANA; DAN CORRAL; BELÉN DOLOTOWICZ; EDUARDO JOSÉ MORAÑA; NEYROLLES, OLIVIER; GEANNCARLO LUGO-VILLARINO; GENOULA, MELANIE; MARIANO MAIO; FEDERICO FUENTES; MATÍAS OSTROWSKI; SASIAIN, MARIA DEL CARMEN
Lugar:
San Miguel de Tucumán
Reunión:
Congreso; LXVII Reunión anual de la sociedad argentina de inmunología 2019; 2019
Resumen:
Since metabolic pathways regulate macrophage biology, they may represent a target for pathogens to circumvent this leukocyte´s effector functions. Macrophage activation towards the pro-inflammatory and microbicidal (M1) program is accompanied by a metabolic shift towards glycolysis and away from oxidative phosphorylation (OXPHOS), a switch that is governed by transcription factor, HIF-1α. Here, we asked whether the microenvironment generated during Mycobacterium tuberculosis infection, the etiological agent for tuberculosis (TB), leads toward changes in the metabolic pathways of M1 macrophages and impairment of microbicidal activity. Our approach was to activate M1 human macrophages using IFN-γ/LPS in the presence of the acellular fraction of tuberculous pleural effusions (PE), a bona fide TB-associated microenvironment. We found that the release of lactate, the final glycolysis product, augmented in M1 macrophages, is reduced in the presence of tuberculous PE. Additionally, these cells displayed an increased mitochondrial respiration and a non-fragmented mitochondrial morphology compared to untreated M1 macrophages. Tuberculous PE also promoted reduced levels of HIF-1α and glycolytic gene expression, lower pro-inflammatory functions including diminished production of mitochondrial radical oxygen species and IL-1β, as well as higher bacillary loads. Strikingly, HIF-1α stabilization through DMOG treatment of macrophages could revert the effect of tuberculous PE. As proof-of-concept, M. tuberculosis-infected mice treated with DMOG displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar and lung interstitial macrophages. In conclusion, we demonstrate that a TB-associated microenvironment alters the metabolic reprogramming of M1 macrophages through hampering HIF-1α functions, resulting in an impaired ability to control M. tuberculosis infection. Keywords: