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

QUIROZ JUAN NAHUEL; BRUGO, MARÍA BELEN; VOLPINI, XIMENA; FONTANARI, CAMILA; STEMPIN, CINTHIA CAROLINA; MOTRAN, CLAUDIA CRISTINA

Congreso; LXX Reunión anual de la Sociedad Argentina de Inmunología (SAI). 16-19 de noviembre. Mar del Plata. Buenos Aires Argentina; 2022

The metabolic programming of immune cells is strongly associatedwith effector functions. Thus, while M1 Mo increase glycolysis (GLY)and reduce oxidative phosphorylation (OXPHOS); M2 Mo relies onOXPHOS and lower GLY rates. Several intracellular pathogens, likeT. cruzi (Tc), exploits host metabolic pathways for their own benefits.Still, targeting host cell metabolism to improve Mo response againstTc represents a new paradigm for parasite control. We reported thatthe activation of Wnt signaling pathways is important for Tc replication inside Mo, since when the secretion of Wnts is blocked withIWPL6, the intracellular replication was inhibited. Whether Wnt signaling has the ability of modulating Tc-infected Mo metabolism issomething that has not been reported. Then, we are focusing in themetabolic 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. Noninfected Mo was set as control. At 72 hpi, Seahorse analyzer andfluorescent probes were used to assess the bioenergetic and mitochondrial status, respectively. Glucose uptake was estimated withglucose 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 Modisplayed an increased OCR-linked basal and maximum respirationat 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 Mocompared to non-infected controls (p<0.05), although they showedincreased 2-NBDG uptake(p<0.05). Nevertheless, when Wnt signaling was arrest, Tc-infected Mo showed higher glycolytic capacitythan the mock-treated counterpart (p<0.05). In summary, Wnt signaling inhibition could switch macrophage metabolic programmingduring Tc infection.