WNT signaling pathway impacts on macrophage (Mo) metabolic programming during Trypanosoma cruzi infection

QUIROZ JN, BRUGO MB, VOLPINI X, FONTANARI C, STEMPIN CC, MOTRAN CC.

Mar del Plata

Congreso; Reunión de Sociedades de Biociencias 2022 - LXX Reunion Anual de la Sociedad Argentina de Imunologia.; 2022

The metabolic programming of immune cells is strongly associated with effector functions. Thus, while M1 Mo increase glycolysis (GLY) and reduce oxidative phosphorylation (OXPHOS); M2 Mo relies on OXPHOS and lower GLY rates. Several intracellular pathogens, like T. cruzi (Tc), exploits host metabolic pathways for their own benefits. Still, targeting host cell metabolism to improve Mo effector functions against Tc represents a new paradigm for parasite control. We reported that the activation of Wnt signaling pathways is important for Tc replication inside Mo, since when the secretion of Wnts is blocked with IWPL6, the intracellular replication was inhibited. Whether Wnt signaling has the ability of modulating Tc-infected Mo metabolism is something that has not been reported. Then, we are focusing in the metabolic characterization of IWPL6-treated Mo during Tc infection. For that, bone marrow derived Mo were treated with IWP-L6 or Vehicle (Mock) for 24 h and then infected with Tc trypomastigotes. Non-infected Mo was used as control. At 72 hpi, Seahorse analyzer and fluorescent probes were used to assess the bioenergetic and mitochondrial status, respectively. Glucose uptake was estimated with glucose analogue 2-NBDG. The frequency of Mo with functional mitochondria were identify as MytoGreenhi MytoOrangehi F4/80+ cells. Compared to control, both mock and IWPL6-treated Tc-infected Mo displayed an increased OCR-linked basal and maximum respiration at 72 hpi (p<0.05) and, higher frequencies of MytoGreenhi MytoOrangehi F4/80+ cells were observed (p<0.05). Moreover, ECAR-related GLY and glycolytic capacity were reduced for Tc-infected Mo compared to non-infected controls (p<0.05), although they showed increased 2-NBDG uptake(p<0.05). Nevertheless, when Wnt signaling was arrest, Tc-infected Mo showed higher glycolytic capacity than the mock-treated counterpart (p<0.05). In summary, Wnt signaling inhibition could switch macrophage metabolic programming during Tc infection.