REWIRING OF MACROPHAGE METABOLISM BY LIPID MEDIATORS DERIVED FROM OMEGA-3 FATTY ACIDS PRESENT IN TUBERCULOUS PLEURAL EFFUSIONS: 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; OLIVIER NEYROLLES; CHRISTEL VÉROLLET; MARÍA DEL CARMEN SASIAIN; LUCIANA BALBOA

Sao Pablo

Congreso; XLVI Congress of the Brazilian Society of Immunology ? Immunometabolism; 2022

Introduction. Previously, we found that proinflammatory (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 the hypoxia-inducible factor (HIF)-1α expression, and ultimately impairing the resistance to infection (Cell Rep. 33-13:108547, 2020). Such properties were driven by polyunsaturated fatty acids metabolites within TB-PE fractions, and herein, we aim to identify them. Methods. Monocytes were obtained from buffy coats at the Garrahan Hospital (Buenos Aires). Pleural effusions and blood samples from TB patients were provided by the Muñiz Hospital after written informed consent (protocol number: 5334/21). Lipids within TB-PE were determined by LC-MS/MS (MetaToul Facility, Toulouse). Monocyte-derived macrophages were stimulated with LPS/IFN-γ for 24h (M1 profile), in the presence or not of commercially available PUFA metabolites. The metabolic profile was assessed by lactate production and the SCENITH method. Bacillary loads from M. tuberculosis-infected macrophages were determined onto 7H11 agar plates at the ANLIS-MALBRAN BSL-3 facility (Buenos Aires). Results. Ex vivo CD14+ cells from pleural effusions of TB patients showed a lower glycolytic capacity and higher mitochondrial dependency than paired CD14+ cells from blood. We found 4 lipids within pleural effusions that were significantly correlated with the in vitro inhibition of M1 macrophages’ glycolysis triggered by each pleural effusion. These 4 lipids namely 18-HEPE, 7(R)-Maresin 1, Protectina Dx and Resolvin D5 were specialized pro-resolving lipids derived from omega-3 fatty acids. We found that RvD5 and 18-HEPE were able to inhibit the release of lactate, increase OXPHOS dependency, and boost M. tuberculosis intracellular growth when added to M1 macrophages at physiological doses found in TB-PE. Interestingly, HIF-1α stabilization obtained after Dimethyloxalylglycine treatment restored the impairment in the release of lactate and microbicidal activities driven by either RvD5 or 18-HEPE in M1 macrophages. Conclusion. So far, we demonstrated that 18-HEPE and RvD5 accumulation in TB-PE contributes to impairing the microbicidal function of M1 macrophages. 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.