CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Mammalian target of rapamycin (mTOR) pathway, a potential regulator of macrophage polarization in Trypanosoma cruzi infection?
Autor/es:
BAIGORRI, R; ROJAS M, JD; STEMPIN C; CERBÁN F
Lugar:
Los Cocos
Reunión:
Congreso; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013
Institución organizadora:
Sociedad Argentina de Inmunología
Resumen:
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.