THE TUBERCULOUS PLEURAL EFFUSION ALTERS THE METABOLIC REPROGRAMMING OF M1 ACTIVATED MACROPHAGES

DUETTE, GABRIEL; NEYROLLES OLIVIER ; SASIAIN MARIA DEL CARMEN ; GENOULA MELANIE; LUGO-VILLARINO GEANNCARLO; PALMERO DOMINGO; BALBOA LUCIANA ; MARÍN JOSÉ LUIS; FERREYRA MALENA ; JOSÉ MORAÑA EDUARDO; SCHIERLOH PABLO

Cancún

Congreso; XII Congress of the Latin American Association of Immunology; 2018

Asociación Latinoamericana de Inmunología

Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections such as Mycobacterium tuberculosis (Mtb), the etiological agent for tuberculosis (TB). Mtb infection remains a major health problem worldwide, with up to 2 billion people chronically infected. The chronic host-pathogen interaction in TB leads to extensive metabolic remodeling in both the host and the pathogen1. In fact, the success of Mtb as a pathogen derives from its efficient adaptation to the intracellular milieu of human macrophages, displaying several strategies to circumvent the microbicidal activity in these cells. Normally, in response to infection, activation of the host immune cells is accompanied by a switch in the bioenergetic pathway from oxidative phosphorylation to aerobic glycolysis, which is required for the production of antimicrobial and pro-inflammatory effector molecules2,3. In this regard, M1 macrophages are known to obtain energy through glycolysis, displaying an increase in glucose uptake as well as the conversion of pyruvate to lactate4. A key transcription factor orchestrating the expression of glycolytic enzymes is the hypoxia-inducible factor-1 (HIF1), a heterodimer comprised of α (HIF-1α) and β (HIF-1β) subunits, being HIF-1α the regulated component of the complex5. The activation of HIF-1α results in the production of pro-inflammatory cytokines and other mediators of the M1 phenotype, such as glycolytic enzymes and the glucose transporter GLUT16. Moreover, at least two interruptions in the Krebs cycle were described in M1 macrophages, leading to the accumulation of intermediates such as succinate. Succinate was known to regulate the stability of HIF-1α driving a sustained production of the proinflammatory cytokine IL-1β7,8. Since M1 macrophage effector functions are deeply related to the metabolic program in course, we hypothesize that Mtb can perturb the metabolic reprogramming in M1 in order to facilitate its intracellular persistence. In this regard, previous reports have demonstrated that the infection with Mtb leads to glycolysis in bone-marrow