Análise das alterações imunológicas nas fases iniciais da doença hepática gordurosa: busca por alternativas para diagnóstico precoce e tratamentos individualizados

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent chronic disease in the world, and limitations in our understanding of its pathogenesis, especially in initial stages, are precluding the development of diagnosis tools and new treatments. Here we mapped the immunological changes in liver during the early stages of fatty liver disease in mice and humans, and proposed a novel mouse model of initial liver steatosis, which may serve as a platform to drive advances in rapid diagnosis and therapeutic fields. For that, liver biopsies from patients in early stages of NAFLD were collected to further profiling of gene expression, and mice received high fat diet for short periods to mimic initial steatosis. Liver immune response in mice was detailed investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. We observed major immunologic changes in both humans and mice in the early phases of liver steatosis. In mice, these changes significantly enhanced mortality rate upon drug-induced liver injury and also predisposed mice to bacterial infections. Also, deletion of TLR4 in liver cells dampened liver tolerogenesis, especially in Kupffer cells, in the initial time points of dietary insult. In conclusion, liver immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon high fat diet insult. Priming of liver immune cells by gut-derived TLR4 ligands may add to liver tolerogenesis in initial phases, but continuous insults may drive hyper-responsiveness to damage and reduced ability to control infections.