THE PLEURAL EFFUSIONS FROM TB PATIENTS ALTER THE METABOLIC REPROGRAMMING OF HUMAN MACROPHAGES BY TARGETING HIF-1A ACTIVITY

MARÍN FRANCO JL; GENOULA M; CORRAL D; DUETTE G; MAIO M; DOLOTOWICZ MB; FERREYRA M; FUENTES F; MORAÑA EJ; PALMERO D; OSTROWSKI M; NEYROLLES O; SCHIERLOH P; SASIAIN MC; LUGO-VILLARINO G; BALBOA L

San Miguel de Tucumán

Congreso; LXVII Reunión Anual de la Sociedad Argentina de Inmunología; 2019

Sociedad Argentina de Inmunología

Since metabolic pathways regulate macrophage biology, they may represent a target forpathogens to circumvent this leukocyte´s effector functions. Macrophage activation towards thepro-inflammatory and microbicidal (M1) program is accompanied by a metabolic shift towardsglycolysis and away from oxidative phosphorylation (OXPHOS), a switch that is governed bytranscription factor, HIF-1α. Here, we asked whether the microenvironment generated duringMycobacterium tuberculosis infection, the etiological agent for tuberculosis (TB), leads towardchanges 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 theacellular fraction of tuberculous pleural effusions (PE), a bona fide TB-associatedmicroenvironment. We found that the release of lactate, the final glycolysis product, augmentedin M1 macrophages is reduced in the presence of tuberculous PE. Additionally, these cellsdisplayed an increased mitochondrial respiration and a non-fragmented mitochondrialmorphology compared to untreated M1 macrophages. Tuberculous PE also promoted reducedlevels of HIF-1α and glycolytic gene expression, lower pro-inflammatory functions includingdiminished production of mitochondrial radical oxygen species and IL-1β, as well as higherbacillary loads. Strikingly, HIF-1α stabilization through DMOG treatment of macrophages couldrevert the effect of tuberculous PE. As proof-of-concept, M. tuberculosis-infected mice treatedwith DMOG displayed lower bacillary loads and a pronounced M1-like metabolic profile inalveolar and lung interstitial macrophages. In conclusion, we demonstrate that a TB-associatedmicroenvironment alters the metabolic reprogramming of M1 macrophages through hamperingHIF-1α functions, resulting in an impaired ability to control M. tuberculosis infection