RESUMO
A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.
Assuntos
Colesterol na Dieta/efeitos adversos , Células de Kupffer/metabolismo , Fígado/imunologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Progressão da Doença , Hepatite/etiologia , Células de Kupffer/ultraestrutura , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , TranscriptomaRESUMO
Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).
Assuntos
Imunidade Adaptativa/fisiologia , Galectinas/metabolismo , Homeostase/imunologia , Hepatopatias/imunologia , Hepatopatias/fisiopatologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/fisiopatologia , Hepatite/imunologia , Hepatite/fisiopatologia , Hepatite Autoimune/imunologia , Hepatite Autoimune/fisiopatologia , Humanos , Imunidade Inata/fisiologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/fisiopatologia , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/fisiopatologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/fisiopatologia , Sensibilidade e EspecificidadeRESUMO
The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD ≤ 20. Neutrophil-to-lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (≥4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case-control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD ≤ 20 within 90 days of death. Controls were similar LT candidates who were alive for ≥90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was ≥ 4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous ≥ 1.9, ≥ 4, ≥ 6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of ≥1.9, ≥ 4, ≥ 6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD. Liver Transplantation 23 155-165 2017 AASLD.
Assuntos
Doença Hepática Terminal/mortalidade , Cirrose Hepática/mortalidade , Transplante de Fígado , Linfócitos , Neutrófilos , Listas de Espera/mortalidade , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Hepática Terminal/sangue , Doença Hepática Terminal/etiologia , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To assess if peripheral T cell populations in children with chronic hepatitis C virus (HCV) infection would show evidence of activation/exhaustion and an attenuated functional response. STUDY DESIGN: Compared with adults, children with HCV infection have a higher rate of spontaneous viral clearance. In adults, chronic HCV has been linked to T cell exhaustion. Little is known of the immune status of children with HCV. Peripheral blood mononuclear cells were isolated from 16 children with HCV (6 males, 10 females; mean age 8.6 years, range 2-17), 16 age- and sex-matched control children without HCV infection, and 20 adults with chronic HCV. Multiparameter flow cytometry was performed to characterize T cell differences across the 3 groups. RESULTS: Controls and children with HCV had similar levels of CD4(+), CD8(+), and γδ(+) T cells. Children with HCV demonstrated a decrease in naïve T cells compared with control children and increased activation/exhaustion marker expression on both CD8(+) and CD4(+) T cells. Transcription factor analysis suggested functional activation of T cells in children with HCV; however, only the CD4(+) subset had enhanced cytokine production (interferon gamma and interleukin-2) compared with control children. CONCLUSIONS: The HCV response in children is characterized by several changes in T cell phenotype. Many of these changes, such as increased T cell expression of programmed cell death-1, are similar to responses in adults. Of note, cytokine production by CD4(+) helper T cells is increased in children with HCV compared with age- and sex-matched control children, which may influence long-term prognosis in children with HCV.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Hepatite C Crônica/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Hepatite C Crônica/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo , Proteínas com Domínio T/metabolismoRESUMO
Liver cirrhosis and hepatocellular carcinoma secondary to chronic hepatitis C virus (HCV) infection requiring transplantation represents a significant public health problem. The most remarkable feature of hepatitis C virus is the ability to establish chronic infection in the vast majority of cases. Efforts to define clinical correlates of HCV persistence have focused primarily on CD4 and CD8 T cell responses. Until recently, the role of innate immunity in determining the outcome of HCV infection had received relatively little attention. Natural killer (NK) cells are an important antiviral effector population eliminating virus through direct killing and cytokine production. Recent studies highlighting the cross-talk between NK cells, dendritic cells (DCs) and T cells have prompted reevaluation of the important role NK cells play in regulating and maintaining specific immune responses. Like many other viruses, HCV has evolved strategies to evade detection and elimination by NK cells. T cell defects observed in HCV infection may be a consequence of inhibition of NK:DC interactions. We propose a theoretical model for HCV persistence that places the NK cell at the center of HCV immune evasion strategies. While this model is only theoretical, it provides a plausible interpretation of many published observations and a useful working model to test the role of NK cells in HCV persistence. In conclusion, the role of innate immune cells and their regulation of antigen-specific responses by the initial innate response to the virus, in particular NK cells, may prove to be an informative and clinically relevant avenue of investigation.