congresos y reuniones científicas
Mammalian target of rapamycin (mTOR) pathway, a potential regulator of macrophage polarization in Trypanosoma cruzi infection?
Los Cocos
Congreso; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013
Institución organizadora:
Sociedad Argentina de Inmunología
Macrophages (Mo) play a key role in the control of intracellular T. cruzi replication. Previously we have shown that T. cruzi modulates Mo polarization through the induction of arginase and upregulation of coinhibitors molecules such as PD-Ls. It is known that mTOR pathway is activated by a decreased in the concentration of amino acids or increased production of urea. Therefore, the aim of this work was to study the role of mTOR in Mo polarization and T. cruzi replication. To do that, Mo from different sources such as J774 cells, Bone Marrow Derived Mo and Peritoneal Mo were pretreated with mTOR pharmacological inhibitors: Rapamicin (Rap), LY294002 and PP242 and then infected with T. cruzi tripomastigotes. While Rap prevents mTOR complex formation, PP242 inhibits its kinase activity and LY294002 is a PI3K inhibitor which is upstream of mTOR. First, we examined the effect of mTOR inhibition in parasite replication. We found that all pretreatment decreased parasite replication (p<0,001) without effect in cellular viability assessed by LDH release. To determine the activation profile of Mo we evaluated arginase expression and activity in pretreated and infected Mo. We observed that Rap decreased arginase activity and down regulated its protein expression. mTOR inhibition was confirmed by reduction in 4EBP-1 and p70S6K phosphorylation. Next, we evaluated the expression of molecules involved in antigen presentation and we found that Rap prevented PD-L1 up-regulation without modification in CD86 expression, changing the balance in costimulatory/co-inhibitory molecules. To assess the role of mTOR in the regulation of pro- and anti-inflammatory cytokines in Mo response against T. cruzi, we determined IL-10 and IL-12p70 production in pretreated and infected Mo. IL-10 production was suppressed (p<0,05) while IL-12p70 production was increased (p<0,05). Taken together, these results suggest that mTOR pathway may be a potential regulator in Mo response during T. cruzi infection.