The immune response as a therapeutic target in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a complex and heterogeneous disorder considered a liver-damaging manifestation of metabolic syndrome. Its prevalence has increased in the last decades due to modern-day lifestyle factors associated with overweight and obesity, making it a relevant public health problem worldwide. The clinical progression of NAFLD is associated with advanced forms of liver injury such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). As such, diverse pharmacological strategies have been implemented over the last few years, principally focused on metabolic pathways involved in NAFLD progression. However, a variable response rate has been observed in NAFLD patients, which is explained by the interindividual heterogeneity of susceptibility to liver damage. In this scenario, it is necessary to search for different therapeutic approaches. It is worth noting that chronic low-grade inflammation constitutes a central mechanism in the pathogenesis and progression of NAFLD, associated with abnormal composition of the intestinal microbiota, increased lymphocyte activation in the intestine and immune effector mechanisms in liver. This review aims to discuss the current knowledge about the role of the immune response in NAFLD development. We have focused mainly on the impact of altered gut-liver-microbiota axis communication on immune cell activation in the intestinal mucosa and the role of subsequent lymphocyte homing to the liver in NAFLD development. We further discuss novel clinical trials that addressed the control of the liver and intestinal immune response to complement current NAFLD therapies.

Keywords: liver diseases; liver fibrosis; liver lymphocyte homing; low-grade inflammation; microbiota; microbiota-gut-liver axis; non-alcoholic fatty liver disease (NAFLD); steatohepatitis (NASH).

Figure 1

The microbiota-gut-liver axis in NAFLD. Interaction diagram of the different mechanisms of the microbiota-gut-liver axis participating in the pathogenesis of NAFLD. (A) Intestinal gut barrier disruption and increased permeability have been demonstrated in patients with NAFLD along with the decreased expression of junctional adhesion molecule A, zonula occludens-1, and occludin. This alteration causes the transfer of pro-inflammatory products and PAMPs (such as LPS or PGN) to the liver circulation, configuring intestinal inflammation and endotoxemia. The translation of PAMPs causes TLR signaling in the mucosa, which leads to the activation of NLRP3. (B) Diet nutrient composition can affect the quantitative and qualitative composition of the gut microbiota, leading to intestinal dysbiosis and bacterial overgrowth, which impacts the immune response, favoring NAFLD progression. Dysbiosis contributes to the disruption of the intestinal barrier, increasing mucosal permeability, which produces more dysbiosis, thereby creating a vicious cycle. Another consequence of dysbiosis is the alteration in the homeostasis of microbe-derived metabolites, such as a decrease in SCFAs and an increase in BAs. (C) The liver is a vital organ in fat metabolization and undergoes many changes in patients with metabolic syndrome, including the over-accumulation of free fatty acid, activation of KCs due to and the TLR4 pathway, lipotoxicity, increased reactive oxygen species and cytokines, and finally, steatosis. Hepatic CCL5 expression levels have been shown to increase in NAFLD patients. The release of the chemokines CCL2 and CCL5 is crucial in the recruitment of lymphocytes to the liver. The migration of mesenteric lymph node cells into the liver is mediated by CCL5, which induces hepatic CD4+ T and CD8+ T cell activation, subsequently leading to liver injury and the progression of NAFLD. BA, Bile acid; CD, Cluster of differentiation; CCL, C-C motif chemokine ligand; KC, Kupffer cell; LPS, Lipopolysaccharide; NAFLD, Non-alcoholic fatty liver disease; NLRP3, NLR family pyrin domain containing 3; PAMP, pathogen-associated molecular pattern; PGN, Peptidoglycan; ROS, Reactive oxygen species; SCFA, Short-chain fatty acid; TLR, Toll-like receptor.

Figure 2

The innate immune response of the gut in NAFLD. Environmental factors such as diet and obesity promote dysbiosis in the gut microbiota, leading to increased levels of PAMPs and impaired intestinal barrier function. The intestinal barrier dysfunction is characterized by the impaired function of several cells, such as goblet cells and Paneth cells, with decreased production of mucin and antimicrobial peptides, respectively. TJ structure and composition disruption also occurs, characterized by reduced ZO-1, ZO-2, and occludin expression. Additionally, alterations of antigen-presenting cell function occur, including decreased phagocytic capacity and increased antigen presentation. These alterations promote increased intestinal permeability and the translocation of PAMPs, leading to increased serum levels of pro-inflammatory cytokines and systemic inflammation. HFD, High-fat diet; IL, Interleukin; LPS, Lipopolysaccharide; NAFLD, Nonalcoholic fatty liver disease; PAMP, pathogen-associated molecular pattern; PGN, Peptidoglycan; TLR, Toll-like receptor; TNF, Tumor necrosis factor.

Figure 3

The gut lymphocyte is homing in the NAFLD liver. Under physiological conditions, dendritic cells imprint gut-homing specificity on T cells in the Peyer’s patches or mesenteric lymph nodes by inducing the upregulation of α4β7 integrin and CCR9. Nevertheless, during NAFLD, the hepatic endothelium aberrantly expresses CCL25 and MAdCAM-1, allowing the pathologic recruitment of gut-primed lymphocytes into the liver. CCL25, C-C motif chemokine ligand 25; CCR9, C-C motif chemokine receptor 9; DC, Dendritic cell; MAdCAM-1, Mucosal addressin cell adhesion molecule 1; NAFLD, Nonalcoholic fatty liver disease.