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Host-Derived Lipids from Tuberculous Pleurisy Impair Macrophage Microbicidal-Associated Metabolic Activity

2020; Cell Press; Volume: 33; Issue: 13 Linguagem: Inglês

10.1016/j.celrep.2020.108547

2639-1856

José Luis Marín Franco, Melanie Genoula, Dan Corral, Gabriel Duette, Malena Ferreyra, Mariano Maio, María Belén Dolotowicz, Omar Emiliano Aparicio‐Trejo, Eduardo Patiño‐Martínez, Alison Charton, Arnaud Métais, Federico Fuentes, Vanessa Soldan, Eduardo José Moraña, Domingo Palmero, Matías Ostrowski, Pablo Schierloh, Carmen Sánchez‐Torres, Rogelio Hernández‐Pando, José Pedraza‐Chaverrí, Yoann Rombouts, Denis Hudrisier, Emilie Layre, Christel Vérollet, Isabelle Maridonneau‐Parini, Olivier Neyrolles, Marı́a del Carmen Sasiain, Geanncarlo Lugo‐Villarino, Luciana Balboa,

Phagocytosis and Immune Regulation

Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host, yet the responsible mechanisms remain elusive. Macrophage activation toward the microbicidal (M1) program depends on the HIF-1α-mediated metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we ask whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We expose M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PEs) and find lower glycolytic activity, accompanied by elevated levels of OXPHOS and bacillary load, compared to controls. The eicosanoid fraction of TB-PE drives these metabolic alterations. HIF-1α stabilization reverts the effect of TB-PE by restoring M1 metabolism. Furthermore, Mtb-infected mice with stabilized HIF-1α display lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages (AMs). Collectively, we demonstrate that lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.