Modulation of metabolic pathways signaling in macrophages infected with Trypanosoma cruzi induce M1-like phenotypes that controls parasite survival

BRUGO, MB; ROJAS MARQUEZ, JD; ANA, Y; STEMPIN, CC; CERBAN, FM

Mar del Plata

Congreso; LXVI Reunión Sociedad Argentina de Inmunología.; 2018

Macrophages (Mo) play a key role in the control of intracellular T.cruzi growth. However, parasite subverts Mo polarization throughmodulation of several signaling pathways to favor its survival. In thisstudy, we focused in metabolic pathways (mTOR and AMPK) andits role during T. cruzi infection in Mo. We have previously shownthat mTOR pathway is activated by T. cruzi, and that its inhibitiondecreased parasite replication in Mo. We observed that, Rapamycin(Rap) (an mTOR inhibitor) pretreated and T. cruzi infected Moshowed reduced nitric oxide (NO) production and iNOS expression.However, those macrophages could control parasite replicationthrough activation of different inflammatory mechanism. Indeed,those Mo showed a significant increase in NLRP3 inflammasomereceptor and IL-1β production. Given that inflammasome could employthe mitochondria as platform of assembly, we found a significantlyincrease in mitochondrial ROS (mtROS) production (3 and 6hpi). To evaluate the relevance of mtROS and inflammasome activation,Bone Marrow Derived Macrophages (BMDM) were treated withDPI (NADPH oxidase inhibitor), or mitoTEMPO (superoxide species[mtROS] scavenger) or CA-074 (cathepsin B inhibitor) and then infectedwith T. cruzi. We observed that mtROS and cathepsin B (aninflammasome activator) inhibition induce significantly higher parasiteload (p<0.05). On the other hand, we found that pretreatmentwith Metformin (Met) (an AMPK activator) in infected Mo showed adecreased in parasite replication (p<0.05). To determinate Mo activation,we evaluate Arginase and iNOS balance in Met pretreatedand infected Mo. We found decreased Arginase activity and expressionand increased NO production and INOS expression, respect tocontrol Mo. This may indicate that Met induces a M1-like phenotype,capable to control parasite replication. Taking together, these resultssuggest that T. cruzi replication could be controlled through modulationof metabolic pathways such as mTOR and AMPK, those allowsmacrophages polarize M1-like phenotypes.