HIF1α-mediated glycolysis promotes the migratory capacity of dendritic cells activated by Mycobacterium tuberculosis

MARIANO MAIO; ZOI VAHLAS; JOAQUINA BARROS; JOSÉ LUIS MARÍN FRANCO; MELANIE GENOULA; FEDERICO FUENTES; GEANNCARLO LUGO VILLARINO; OLIVIER NEYROLLES; MARÍA DEL CARMEN SASIAIN; CHRISTEL VEROLLET; LUCIANA BALBOA

Congreso; CTVD; 2022

Mycobacterium tuberculosis (Mtb) is a highly successful pathogen that interferes with dendritic cells (DCs) functions impairing the onset and development of adaptive immunity. Since several studies are now revealing the importance of metabolic pathways involved in DCs functions, we wondered how the metabolic pathways influence DCs activation in response to Mtb. Herein, we found that monocyte-derived DCs from healthy donors stimulated with equivalent doses of either irradiated Mtb (iMtb) or viable Mtb released lactate and consumed glucose at higher rates than untreated-DCs. In line with it, either iMtb- or Mtb-treatment resulted in the upregulation of HIF-1α expression at protein and mRNA levels, as well as the glycolytic enzyme LDHA. According to Seahorse and SCENITH technology approaches, Mtb-activated DCs displayed a predominant glycolytic profile in a TLR2-dependent manner. Additionally, Mtb-triggered HIF-1α activity is required for DCs to adopt a mature phenotype and chemotactic activity against CCL21, but not to differentially polarize Th cells. Interestingly, the treatment of Mtb-stimulated DCs with reagents which are known to inhibit glycolysis, such as drug GSK28378 or sodium oxamate, resulted in a lower chemotactic activity towards CCL21 (CCR7 ligand) and a reduced amoeboid migration through fibrillar collagen, suggesting that HIF-1α-mediated glycolysis is required for DCs mobilization to the lymph nodes. Finally, we showed that the stabilization of HIF-1α promoted immunogenic features in tolerogenic DCs induced by dexamethasone upon iMtb stimulation in terms of surface expression markers, cytokines production and lactate release. Remarkably, the migration towards CCL21 as well as the 3D-migration of cells throughout the collagen matrix were enhanced by the stabilization of HIF-1α using dimethyloxalylglycine (DMOG) in tolerogenic DCs stimulated with Mtb. Therefore, the modulation of the glycolytic pathway is key to foster the migratory capacity of monocyte-derived DCs activated by Mtb. Our data provide novel insights into immunometabolic pathways involved in the trafficking of Mtb-activated DCs to the lymph nodes that could be targeted to generate sterilizing vaccine-induced immunity against TB.