The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance.

Figure 1

Correlation between the prevalence of obesity and NAFLD in the Americas. The graph was built with data from the prevalence of obesity for each country; NAFLD prevalence was estimated assuming that about 80% of obese patients might develop NAFLD in the Americas countries. Reproduced with permission of the journal [1].

Figure 2

Schematic mechanisms involved in the progression of NAFLD to NASH. Lifestyle factors such as obesity and genetic predispositions contributing to the development of insulin resistance and hepatic steatosis. In the following steps multiple parallel metabolic hits lead to cellular damage, via a process called “lipotoxicity.” Injured hepatocytes initiate an inflammatory response, predominantly via toll-like receptors, and activate proinflammatory signaling pathways in the setting of increased adipokine levels. Also the apoptosis and senescence are alternative cell fates that are likely to be of greater importance to disease progression. Direct recruitment of Kupffer cells and other components of the innate immune response such as dendritic cells occurs with activation of the inflammasome and the coordinated release of proinflammatory and profibrogenic cytokines and ligands. Hepatic stellate cells (HSCs) are subsequently activated to produce extracellular matrix leading to progressive fibrosis and cirrhosis and its complications such as hepatocellular carcinoma (HCC).

Figure 3

Immunohistochemistry for hepatic dendritic cells. Some dendritic cells are CD11C positive (large arrow) in a patient with nonalcoholic fatty liver disease. The vast majority of hepatocytes contained vacuoles of lipids (small arrow) (grade 3 micro- and macrovesicular steatosis) (×400).