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...

Infection with protozoan parasite Trypanosoma cruzi results in activation of nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs). NLR activation leads to inflammasome formation, the activation of caspase-1, and the subsequent cleavage of IL-1β and IL-18. Considering that inflammasome activation and IL-1β induction by macrophages are key players for an appropriate T cell response, we investigated the relevance of NLR pyrin domain-containing 3 (NLRP3) and caspase-1/11 to elucidate their roles in the induction of different T cell phenotypes and the relationship with parasite load and hepatic inflammation during T. cruzi-Tulahuen strain acute infection. We demonstrated that infected nlrp3−/− and C57BL/6 wild type (WT) mice exhibited similar parasitemia and survival, although the parasite load was higher in the livers of nlrp3−/− mice than in those of WT mice. Increased levels of transaminases and pro-inflammatory cytokines were found in the plasma of WT and nlrp3−/− mice indicating that NLRP3 is dispensable to control the parasitemia but it is required for a better clearance of parasites in the liver. Importantly, we have found that NLRP3 and caspase-1/11-deficient mice differentially modulate T helper (Th1, Th2, and Th17) and cytotoxic T lymphocyte phenotypes. Strikingly, caspase-1/11−/− mice showed the most dramatic reduction in the number of IFN-γ- and IL-17-producing CD4+ and CD8+ T cells associated with higher parasitemia and lower survival. Additionally, caspase-1/11−/− mice demonstrated significantly reduced liver inflammation with the lowest alanine aminotransferase (ALT) levels but the highest hepatic parasitic load. These results unequivocally demonstrate that caspase-1/11 pathway plays an important role in the induction of liver adaptive immunity against this parasite infection as well as in hepatic inflammation.

BackgroundThe immune mechanisms underlying experimental non-alcoholic steatohepatitis (NASH), and more interestingly, the effect of T. cruzi chronic infection on the pathogenesis of this metabolic disorder are not completely understood.Methodology/Principal FindingsWe evaluated immunological parameters in male C57BL/6 wild type and TLR4 deficient mice fed with a standard, low fat diet, LFD (3% fat) as control group, or a medium fat diet, MFD (14% fat) in order to induce NASH, or mice infected intraperitoneally with 100 blood-derived trypomastigotes of Tulahuen strain and also fed with LFD (I+LFD) or MFD (I+MFD) for 24 weeks. We demonstrated that MFD by itself was able to induce NASH in WT mice and that parasitic infection induced marked metabolic changes with reduction of body weight and steatosis revealed by histological studies. The I+MFD group also improved insulin resistance, demonstrated by homeostasis model assessment of insulin resistance (HOMA-IR) analysis; although parasitic infection increased the triglycerides and cholesterol plasma levels. In addition, hepatic M1 inflammatory macrophages and cytotoxic T cells showed intracellular inflammatory cytokines which were associated with high levels of IL6, IFNγ and IL17 plasmatic cytokines and CCL2 chemokine. These findings correlated with an increase in hepatic parasite load in I+MFD group demonstrated by qPCR assays. The recruitment of hepatic B lymphocytes, NK and dendritic cells was enhanced by MFD, and it was intensified by parasitic infection. These results were TLR4 signaling dependent. Flow cytometry and confocal microscopy analysis demonstrated that the reactive oxygen species and peroxinitrites produced by liver inflammatory leukocytes of MFD group were also exacerbated by parasitic infection in our NASH model.ConclusionsWe highlight that a medium fat diet by itself is able to induce steatohepatitis. Our results also suggest a synergic effect between damage associated with molecular patterns generated during NASH and parasitic infection, revealing an intense cross-talk between metabolically active tissues, such as the liver, and the immune system. Thus, T. cruzi infection must be considered as an additional risk factor since exacerbates the inflammation and accelerates the development of hepatic injury.

No abstract