Myeloid-derived suppressor cells (MDSCs Keywords: Inflammation r MDSCs r Nitric oxide r ROS r Trypanosoma cruziAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMyeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population consisting of immature macrophages, granulocytes, and dendritic cells as well as myeloid progenitor cells. They are considered to be one of the major components of the immune suppressive network responsible for suppressing T-cell responses in pathological conditions [1,2] as well as in the regulation of the immune response in healthy individuals [3]. These Correspondence: Dr. Susana Gea e-mail: sgea@fcq.unc.edu.ar myeloid cells are commonly identified in mice by the co-expression of the surface markers CD11b and Gr1 (Ly6G/Ly6C) and have been divided into two subsets: granulocytic (G) MDSCs with a CD11b + LY6G + LY6C low phenotype and monocytic (M) MDSCs with CD11b + LY6G − LY6C high phenotype [3,4]. Despite their morphological similarities, G-MDSCs and neutrophils are functionally and phenotypically different. G-MDSCs, but not neutrophils, are immunosuppressive and express higher levels of arginase-1 and myeloperoxidase than neutrophils, and also have increased production of reactive oxygen species (ROS) [5,6]. Although * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2014. 44: 184-194 Immunomodulation 185 M-MDSCs and inflammatory monocytes share the same phenotype and morphology, these cells are functionally distinct since M-MDSCs are highly immunosuppressive and they express high levels of both iNOS and arginase-1. Furthermore, although iNOS expression is a hallmark of a tumoricidal/microbicidal phenotype in M1 macrophages, iNOS promotes suppressive activities in M-MDSCs. This shift in iNOS activity most likely reflects the crosstalk of iNOS with other enzymes such as NADPH oxidase to promote the production of peroxynitrites, which inhibits the proliferation and effector function of T cells [2]. MDSCs use several mechanisms in addition to the production of ROS and NO, such as triggering apoptosis of activated T cells by depleting of L-arginine, via arginase [7][8][9][10]. There is also evidence that MDSCs may suppress immune activation by inducing T regulatory cell expansion [11]. Other suppressive mechanisms that have recently been proposed include the production of TGF-β [12,13], depletion of cysteine [8], induction of COX2 and prostaglandin E2 [1,[14][15][16].Trypanosoma cruzi an obligate intracellular protozoan, is the causative agent of Chagas disease. This disease affects about 20 million people in Latin America, with 120 million persons at risk. In the past decades, mainly as a result of increased migrations, the diagnosed cases have also increased in nonendemic countries such as Canada, United States of America, and Europe. This has led to an increased risk of transmission of the infection, mainly through blood transfusion and organ transplantation [17]. Pa...

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The production of nitric oxide (NO) is a key defense mechanism against intracellular pathogens but it must be tightly controlled in order to avoid excessive detrimental oxidative stress. In this study we described a novel mechanism through which interleukin (IL)-6 mediates the regulation of NO release induced in response to Trypanosoma cruzi infection. Using a murine model of Chagas disease, we found that, in contrast to C57BL/6 wild type (WT) mice, IL-6-deficient (IL6KO) mice exhibited a dramatic increase in plasma NO levels concomitant with a significantly higher amount of circulating IL-1β and inflammatory monocytes. Studies on mouse macrophages and human monocytes, revealed that IL-6 decreased LPS-induced NO production but this effect was abrogated in the presence of anti-IL-1β and in macrophages deficient in the NLRP3 inflammasome. In accordance, while infected WT myocardium exhibited an early shift from microbicidal/M1 to anti-inflammatory/M2 macrophage phenotype, IL6KO cardiac tissue never displayed a dominant M2 macrophage profile that correlated with decreased expression of ATP metabolic machinery and a lower cardiac parasite burden. The deleterious effects of high NO production-induced oxidative stress were evidenced by enhanced cardiac malondialdehyde levels, myocardial cell death and mortality. The survival rate was improved by the treatment of IL-6-deficient mice with a NO production-specific inhibitor. Our data revealed that IL-6 regulates the excessive release of NO through IL-1β inhibition and determines the establishment of an M2 macrophage profile within infected heart tissue.