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

Mar del Plata

Congreso; LXII REUNIÓN ANUAL Sociedad Argentina de Inmunología; 2014

Sociedad Argentina de Inmunología

Chagas disease caused by the protozoan parasite Trypanosoma cruzi is an important cause of heart disease in endemic areas of Latin America but the person migrations have favored its spreading in non-endemic countries. Parasite persistence eventually results in severe complications in the cardiac and gastrointestinal tissues although this protozoan also infects the liver and the spleen. Nonalcoholic steatohepatitis (NASH) constitutes a prominent health concern with increasing incidence of obesity and diabetes in the world and is characterized by the presence of steatosis, inflammation and hepatocyte injury. The immune mechanisms underlying in experimental steatohepatitis and more interestingly the effect of T. cruzi chronic infection on the pathogenesis of this metabolic disorder are not completely understood. In our laboratory we developed a physiological model of NASH. mmice C57BL/6 WT and TLR4-/- (n=6/group) were fed for 24 weeks with: LFD, low fat diet (3% fat) as control group; MFD, medium fat diet (14% fat); I+LFD and I+MFD. The infected groups (I) received i.p. 100 trypomastigotes (Tulahuén). We demonstrated that MFD by itself is able to induce NASH in WT mice and parasitic infection induced marked metabolic changes with body weight (p< 0,001 MFD vs. I+MFD) and steatosis reduction. It also improved insulin resistance evaluated by HOMA-IR but parasite infection increased the plasma triglycerides and cholesterol levels. Liver M1 inflammatory macrophages and cytotoxic T cells purified from intrahepatic leukocytes (IHLs) were significantly elevated in all experimental groups and showed intracellular inflammatory cytokines which were associated with high levels of plasma IL6, IFNγ and IL17 inflammatory cytokines and CCL2 chemokine (p<0.01). 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. The reactive oxygen species and peroxinitrites produced by IHLs and FASL expression in MFD group were also exacerbated by parasite infection. Our results 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 liver and the immune system. Thus, T. cruzi infection must be considered as an additional risk factor since exacerbate the inflammation and accelerate the development of hepatic injury