Myeloid-derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

Abstract

Myeloid-derived suppressor cells (MDSCs) are key players in the immune suppressive network. During acute infection with the causative agent of Chagas disease, Trypanosoma cruzi, BALB/c mice show less inflammation and better survival than C57BL/6 (B6) mice. In this comparative study, we found a higher number of MDSCs in the spleens and livers of infected BALB/c mice compared with infected B6 mice. An analysis of the two major MDSCs subsets revealed a greater number of granulocytic cells in the spleens and livers of BALB/c mice when compared with that in B6 mice. Moreover, splenic MDSCs purified from infected BALB/c mice inhibited ConA-induced splenocyte proliferation. Mechanistic studies demonstrated that ROS and nitric oxide were involved in the suppressive activity of MDSCs, with a higher number of infected CD8(+) T cells suffering surface-nitration compared to uninfected controls. An upregulation of NADPH oxidase p47 phox subunit and p-STAT3 occurred in MDSCs and infected IL-6 KO mice showed less recruitment of MDSCs and impaired survival. Remarkably, in vivo depletion of MDSCs led to increased production of IL-6, IFN-γ, and a Th17 response with very high parasitemia and mortality. These findings demonstrate a new facet of MDSCs as crucial regulators of inflammation during T. cruzi infection.

Keywords: Inflammation; MDSCs; Nitric oxide; ROS; Trypanosoma cruzi.