Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD.
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Diniz Ariane Barros, Antunes Maísa Mota, Lacerda Viviane Aparecida de Souza, Nakagaki Brenda Naemi, Freitas Lopes Maria Alice, Castro-Oliveira Hortência Maciel de, Mattos Matheus Silvério, Mafra Kassiana, de Miranda Camila Dutra Moreira, de Oliveira Costa Karen Marques, Lopes Mateus Eustáquio, Alvarenga Débora Moreira, Carvalho-Gontijo Raquel, Marchesi Sarah Cozzer, Lacerda Debora Romualdo, de Araújo Alan Moreira, de Carvalho Érika, David Bruna Araújo, Santos Mônica Morais, Lima Cristiano Xavier, Silva Gomes Juliana Assis, Minto Fontes Cal Tereza Cristina, de Souza Bruna Roque, Couto Cláudia Alves, Faria Luciana Costa, Teixeira Vidigal Paula Vieira, Matos Ferreira Adaliene Versiane, Radhakrishnnan Sridhar, Ricci Matthew, Oliveira André Gustavo, Rezende Rafael Machado, Menezes Gustavo Batista
Аннотация
METHODS: Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2-3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays.
RESULTS: We observed major immunologic changes in patients with NAS 2-3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult.
CONCLUSION: The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections.
LAY SUMMARY: Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease.