Impact of the macrophage activation state on the accumulation of lipid bodies induced by the tuberculous pleurisy milieu

DENISE KVIATCOVSKY; E. MORAÑA; E. GONZALEZ-DOMINGUEZ; PAULA. BARRIONUEVO; MELANIE GENOULA; BELEN IMPERIALE; D. MATA-ESPINOZA; ROGELIO HERNÁNDEZ-PANDO; LUCIANA BALBOA; AYELEN MILILLO; PABLO GONZALEZ-MONTANER; C. SANCHEZ TORRES; MARIA DEL CARMEN SASIAIN

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Inmunología; 2016

Sociedad Argentina de Inmunología

During intracellular bacterial infection, the eukaryotic cells show metabolic adaptations that help them to eliminate the pathogen and conversely, the pathogen tries to profit from host metabolites. The ability of Mycobacterium tuberculosis (Mtb) to persist relies on its numerous immune evasion strategies such as the dysregulation of the lipid metabolism that can lead to foamy macrophage (FM) differentiation. So far, the specific host factors leading to FM induction are unknown. We aimed to characterize whether different profiles of macrophage (M0, M1, M2a, and M2c) differ in their propensity to accumulate lipid bodies (LB) upon exposure to tuberculous pleural effusions (TB-PE). For that, LB accumulation was evaluated by oil red staining, cytokines by ELISA, pSTAT-3 and ACAT by western blot, cholesterol by enzymatic assays, and bacillary loads by colony-forming units assay.TB-PE induced a FM phenotype in M0, M2c and M1 but not in M2a (n=8). After depleting IL-10, IL-4, IFN-g, IL-1b, IL-6, or TNF-a from TB-PE, only IL-10 depletion prevented FM differentiation (n=8). TB-PE increased the levels of intracellular cholesterol, while IL-10 depletion reduced it. Besides, PE-TB or IL-10 addition induced CD36 expression, which mediates lipids uptake, and also pSTAT-3 levels, which governs the M2c program (n=5); moreover, pSTAT-3 inhibition prevented LB accumulation (n=4). Interestingly, the expression of ACAT, the enzyme that synthesizes cholesteryl esters, was induced by TB-PE in any macrophage profile except for M2a. Finally, TB-PE promoted the intracellular growth of Mtb in macrophages in an IL-10 dependent manner but not in M2a (n=10). Therefore, macrophage profiles differ in their propensity to accumulate LB, process that requires the activation of the IL-10/STAT-3 axis and favours Mtb replication. M2a was refractory to FM differentiation lacking ACAT expression. These results contribute to our understanding of the host metabolic alterations driven by Mtb.