CONICET | Buscador de Institutos y Recursos Humanos

Tuberculosis remains a major global health problem accounting for millions of deaths annually. Its causative agent, Mycobacterium tuberculosis (Mtb), is a highly successful pathogen that interferes with dendritic cells (DC) functions impairing the onset and development of adaptive immunity. Several studies are now revealing the importance of metabolic pathways involved in the modulation of DC diﬀerentiation, e.g. activated DCs are known to switch to glycolysis through HIF-1α activation, while the role of the fatty acid oxidation (FAO) remains unclear. Herein we wondered how metabolic pathways influence DC activation in response to Mtb. For this purpose, we treated monocyte-derived DC with DMOG (HIF-1α activator), Etomoxir (FAO inhibitor) or L-carnitine (FAO enhancer), stimulated them or not with irradiated Mtb (iMtb) and evaluated surface markers expression by FACS, lactate release by enzymatic assays, and cytokines` production by ELISA. While DMOG potentiated the release of lactate in iMtb-stimulated DC, Etomoxir reduced it promoting the expression of the inhibitory molecule PD-L1 and the production of IL-10. Then, we evaluated the capacity of DMOG and L-carnitine to inhibit the generation of tolerogenic DC. We found that DMOG inhibited tolerogenic features in dexamethasone-treated DC (Dx-DC) by reducing IL-10 levels and promoting lactate and TNF-α levels as well as CD83 and CD86 expression upon iMtb stimulation. Besides, L-carnitine treatment resulted in lower IL-10 levels and higher CD86 expression in Dx-DC. In conclusion, the inhibition of FAO during Mtb stimulation contributes to the establishment of a tolerogenic phenotype, while the stabilization of HIF-1α promotes immunogenic features in Mtb-stimulated DC. Keywords: dendritic cells, tuberculosis, immunometabolism, HIF-1α