Metformin regulates inflammatory response of T. cruzi-infected peritoneal macrophages in an ex vivo treatment model.

BAIGORRI, RUTH ELIANA; ANA, YAMILE; BRUGO, MARÍA BELÉN; VOLPINI, XIMENA; MOTRÁN, CRISTINA; STEMPIN, CINTHIA CAROLINA; CERBAN, FABIO MARCELO

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020; 2020

During the acute phase of T. cruzi infection, high replication of the parasite is controlled by a strong inflammatory response with activation of the innate immune cells due to increase of Th1 proinflammatory cytokines. Macrophages (Mø) have been described to control intracellular parasite replication when iNOS expression and ON production are induced in vitro. We previously reported that pretreatment of bone marrow derived Mø with Metformin (Metf) leads these cells to control parasite replication presumably by modulating inflammasome activation without increase of iNOS expression. However, it has been demonstrated that high and continuous ON release by Mø and other cells, is involved in Th1 T cell suppression. In this context, Metf was associated to reduce inflammatory-related ischemic cardiovascular events, prolong lifespan and decrease aged-related inflammation. To determine the Mø activation profile during in vivo T. cruzi infection and the possibles effects of Metf treatment, we tested iNOS expression by FACS in Peritoneal Mø (Pe-Mø) subsets, LPM (Large Pe-Mø) and SPM (Small Pe-Mø). We observed increased iNOS expression (p<0.001) in LPM and SPM during the acute phase (day 20 post infection) that declines around day 40, despite the high ON levels in plasma at this point. To determine other sources of ON production we assessed iNOS expression in spleen cells by FACS and we found small but consistent F4/80+CD11b+iNOS+ cells. After that, we performed an ex vivo treatment of total Pe-Mø from infected mice in acute phase and we observed a decrease in supernatants levels of ON and TNF-a levels by ELISA (p<0,05) when cells are exposed to Metf. To test if Metf polarize Mø to an antiinflammatory profile, we tested arginase expression by WB and IL-10 production by ELISA but we observe no changes in these parameters. Taken together, these results suggest that Metf could modulate exacerbated Mø activation during high parasitaemia acute phase that could lead to organ damage.