REWIRING OF MACROPHAGE METABOLISM BY LIPID MEDIATORS DERIVED FROM OMEGA-3 FATTY ACIDS: ITS IMPACT ON THE CONTROL OF MYCOBACTERIUM TUBERCULOSIS INFECTION

JOAQUINA BARROS; MARIANO MAIO; JOSÉ LUIS MARÍN FRANCO; MARINE JOLY; DOMINGO PALMERO; XAVIER ARAGONE; EMILIE LAYRE; GEANNCARLO LUGO VILLARINO; RAFAEL J ARGÜELLO; OLIVIER NEYROLLES; CHRISTEL VÉROLLET; MARÍA DEL CARMEN SASIAIN ; LUCIANA BALBOA

Congreso; VALIDATE Annual Meeting; 2023

The success of M. tuberculosis (Mtb) as a pathogen derives from its efficient adaptation to the intracellular milieu of macrophages, entailing the regulation of their metabolic pathways. Previously, we found that M1 macrophages exposed to the acellular fraction of pleural effusions from TB patients (TB-PE) displayed a reduced glycolytic activity and an increased mitochondrial respiration by targeting HIF-1α expression, and ultimately impairing the resistance to infection. Such properties were driven by polyunsaturated fatty acids (PUFA) metabolites, and herein, we aim to identify them. For this purpose, were determined PUFA metabolites within TB-PE by LC-MS/MS. The abundances of the omega-3-derived pro-resolving mediators 18-HEPE, 7(R)-Maresin 1, Protectin Dx and Resolvin D5 correlated with the inhibition of M1 macrophages’ glycolysis. To explore their implication in the regulation of the M1 metabolism, monocyte-derived macrophages were stimulated with LPS/IFN-γ for 24h (M1 profile) in the presence or not of those lipids, and the metabolic profile was assessed by the SCENITH method. Alternatively, macrophages were infected with Mtb. Unlike 7MaR1 and PDx, RvD5 and 18-HEPE reduced the glycolytic activity by M1 macrophages, leading to an increased mitochondrial respiration as well as high intracellular bacillary loads, features that could be reverted after the chemical stabilization of HIF-1α. Finally, we determined the ex vivo metabolism of CD14+ cells from paired TB pleural effusions and blood samples and found that pleural CD14+ cells showed a lower glycolytic capacity and a higher mitochondrial dependency than their blood counterpart. Unraveling the mechanisms by which lipids found in a TB microenvironment can drive metabolic alterations of macrophages leading to poor local protection will significantly advance knowledge on TB immunity.