IL-6 drives cardiac macrophage profile and regulates the lethal release of Nitric Oxide through IL- 1β inhibition during parasite infection

SANMARCO L.M.; PONCE N.E.; EBERHARDT N.; AOKI M.P.

Buenos Aires

Congreso; LASID 2015; 2015

Monocytes/Macrophages are a heterogeneous population of immune cells that have arange of roles in the induction and resolution of inflammation. The nitric oxide (NO) production isassociated with the killing of microorganisms and characterizes M1-type macrophage response. Thefactors involved in cardiac macrophage profile differentiation during T. cruzi infection have not beencharacterized. The aim of the present work was to study whether myocardial IL-6 production candetermine the influx and phenotype of macrophage subpopulations and influence tissueinjury/regeneration during T. cruzi acute infection. We observed that infected C57BL/6 mice (WT)exhibited higher cardiac M1 (CD11b+F4/80+CD86+CD206-) macrophage number than M2(CD11b+F4/80+CD86-CD206+) (p<0.05) at 4 days post-infection (dpi), but later the macrophagepopulation was biased to sustained M2 subset. In contrast, IL6KO mice never displayed a dominant M2profile that correlated with less cardiac parasite burden at 21dpi (p<0.001). Concomitantly they exhibiteda dramatic increase in serum levels of NO and the pro-inflammatory cytokine IL-1b at 4dpi (p<0.001 andp<0.05 respectively) and 21dpi (p<0.05 and p<0001 respectively) compared to WT. Studies on mouseand human macrophages revealed that IL-6 stimulation decreased the release of LPS-induced NOproduction (p<0.05 and p<0.001) but this effect was abrogated in the presence of anti-IL-1β and inNLRP3KO macrophages. Our data suggest that IL-6 would have a key role in regulating the lethalrelease of NO thought IL-1β inhibition, and underline the importance of understanding the pleiotropiceffect of IL-6, given the fact that this cytokine is a therapeutic target in patients with differentimmunopathologies.