Immunomodulation in non-alcoholic fatty liver disease: exploring mechanisms and applications

Abstract

Non-alcoholic fatty liver disease (NAFLD) exhibits increased lipid enrichment in hepatocytes. The spectrum of this disease includes stages such as nonalcoholic simple fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and liver fibrosis. Changes in lifestyle behaviors have been a major factor contributing to the increased cases of NAFLD patients globally. Therefore, it is imperative to explore the pathogenesis of NAFLD, identify therapeutic targets, and develop new strategies to improve the clinical management of the disease. Immunoregulation is a strategy through which the organism recognizes and eliminates antigenic foreign bodies to maintain physiological homeostasis. In this process, multiple factors, including immune cells, signaling molecules, and cytokines, play a role in governing the evolution of NAFLD. This review seeks to encapsulate the advancements in research regarding immune regulation in NAFLD, spanning from underlying mechanisms to practical applications.

Keywords: Kupffer cells; NASH; immune cells; immunoregulation; non-alcoholic fatty liver disease.

Figure 1

NAFLD progression and cell-to-cell signaling. (A) Development and progression of Healthy liver to HCC. Healthy liver can develop into NAFL, NASH, liver fibrosis, liver cirrhosis and/or HCC due to several factors. (B) HCC: hepatocellular carcinoma; Major cell type distribution in the liver and their known functions. (C) Pathogenesis of NAFLD. NAFLD, non-alcoholic fatty liver disease; NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; SFAs, saturated fatty acids; ER stress, endoplasmic reticulum stress; ATP, adenosine-triphosphate.

Figure 2

Role of innate immune cells in NAFLD and NASH. During the progression of non-alcoholic steatohepatitis NASH, KCs can be activated by circulating FFAs and cytokines from inflamed obese adipose tissue, PAMPs from the microbiota, and DAMPs released by damaged hepatocytes. Activated KCs contribute to hepatic steatosis by influencing lipid metabolism in hepatocytes. Furthermore, activated KCs amplify the inflammatory response by secreting TNF and CCL2, thereby enhancing the CCR2-dependent recruitment of monocytes into the liver. Infiltrating monocytes, in turn, secrete pro-inflammatory MoMFs, fostering the progression of NASH and fibrosis. The cytokines TNF, IL-1β, and TGF-β1 produced by activated KCs and macrophages contribute to the activation of HSCs. Neutrophils are recruited to the liver and accumulate in chronically inflamed tissues during NASH. NETosis and neutrophil activation lead to the release of granule proteins, including NE, LCN2, and MPO thereby contributing to hepatic steatosis, increased inflammation, and fibrosis. NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; KCs, Kupffer cells; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TNF, tumor necrosis factor; CCL2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor type 2; MoMFs, monocyte-derived macrophages; IL-1β, interleukin 1 beta; TGF-β1, transforming growth factor-beta; HSCs, hepatic stellate cells; NE, neutrophil elastase; MPO, myeloperoxidase; LCN2, lipocalin 2.

Figure 3

Neutrophil Production, Monocyte recruitment and differentiation into macrophages and Macrophage polarization. Th1, T helper cell 1; Th2, T helper cell 2; M0, Macrophages 0; M1, Macrophages 1; M2, Macrophages 2; IL, Interleukin; CCL, chemotactic cytokines; CXCL, C-X-C motif chemokine ligand; NK cells, Natural killer T cells; IFN-γ, Interferon-γ; TGF-β, Transforming growth factor-β; TNF-α, Tumor necrosis factor-alpha; NO, Nitric oxide; ROS, Reactive oxygen species.