Abstract
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.
Highlights
The liver is a key organ that controls the metabolic homeostasis of lipids, carbohydrates, and proteins
Our results suggest a synergic effect between damage associated with molecular patterns generated during non-alcoholic steatohepatitis (NASH) and parasitic infection, revealing an intense cross-talk between metabolically active tissues, such as the liver, and the immune system
Our findings demonstrate for the first time a synergic effect between the hepatic damage caused during the steatohepatitis process and the exacerbated inflammation triggered by the chronic parasitic infection, revealing an intense cross-talk between the liver, a metabolically active tissue, and the immune system
Summary
The liver is a key organ that controls the metabolic homeostasis of lipids, carbohydrates, and proteins. NASH is considered to be a chronic inflammatory liver disease influenced by risk factors of the metabolic syndrome [8] and by the insulin resistance (IR) associated with steatosis, overweight, dyslipidaemia, hyperinsulinaemia, and arterial hypertension [9]. Inflammation is imposed on steatosis by recruitment and activation of inflammatory cells in the liver, which contributes to steatohepatitis [10] This phenomenon can be explained by increased lipolysis from the fat cells or increased intake of dietary fat, followed by the enrichment of free fatty acids (FFA). The 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
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