Trypanosoma cruzi infection is a potent risk factor for non-alcoholic steatohepatitis enhancing local and systemic inflammation associated with strong oxidative stress and metabolic disorders

ONOFRIO LUISINA; AROCENA ALFREDO; PAROLI AUGUSTO; CABALÉN, MARÍA E.; ANDRADA MARTA C; CANO, ROXANA C. ; GEA, SUSANA

PLOS NEGLECTED TROPICAL DISEASES

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2014

1935-2735

BackgroundThe immune mechanisms underlying experimental non-alcoholic steatohepatitis (NASH),and more interestingly, the effect of T. cruzi chronic infection on the pathogenesis of thismetabolic disorder are not completely understood.Methodology/Principal FindingsWe evaluated immunological parameters in male C57BL/6 wild type and TLR4 deficientmice 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 bloodderivedtrypomastigotes 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 miceand that parasitic infection induced marked metabolic changes with reduction of bodyweight and steatosis revealed by histological studies. The I+MFD group also improved insulinresistance, demonstrated by homeostasis model assessment of insulin resistance(HOMA-IR) analysis; although parasitic infection increased the triglycerides and cholesterolplasma levels. In addition, hepatic M1 inflammatory macrophages and cytotoxic T cellsshowed intracellular inflammatory cytokines which were associated with high levels of IL6,IFNγ and IL17 plasmatic cytokines and CCL2 chemokine. These findings correlated with anincrease in hepatic parasite load in I+MFD group demonstrated by qPCR assays. The recruitmentof hepatic B lymphocytes, NK and dendritic cells was enhanced by MFD, and itwas intensified by parasitic infection. These results were TLR4 signaling dependent. Flowcytometry and confocal microscopy analysis demonstrated that the reactive oxygen species and peroxinitrites produced by liver inflammatory leukocytes of MFD group were also exacerbatedby parasitic infection in our NASH model.ConclusionsWe highlight that a medium fat diet by itself is able to induce steatohepatitis. Our resultsalso suggest a synergic effect between damage associated with molecular patterns generatedduring NASH and parasitic infection, revealing an intense cross-talk between metabolicallyactive tissues, such as the liver, and the immune system. Thus, T. cruzi infection mustbe considered as an additional risk factor since exacerbates the inflammation and acceleratesthe development of hepatic injury.