Innate immunity and nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), recently renamed as metabolic (dysfunction)-associated fatty liver disease (MAFLD), is a complex, multifactorial disease that progresses via nonalcoholic steatohepatitis (NASH) towards severe liver complications. MAFLD/NAFLD affects up to a third of the global population. It is connected with metabolic syndrome parameters and has been increasing in parallel with the rates of metabolic syndrome parameters worldwide. This disease entity exhibits a strong immune-inflammatory dimension. In MAFLD/NAFLD/NASH, a vast network of innate immune cells is mobilized that can provoke liver damage, leading to advanced fibrosis, cirrhosis and its complications, including hepatocellular carcinoma. However, our understanding of the inflammatory signals that drive the onset and progression of MAFLD/NAFLD/NASH is fragmented. Thus, further investigation is required to better understand the role of specific innate immune cell subsets in the disease, and to aid the design of innovative therapeutic agents to target MAFLD/NAFLD/NASH. In this review, we discuss current concepts regarding the role of innate immune system involvement in MAFLD/NAFLD/NASH onset and progression, along with presenting potential stress signals affecting immune tolerance that may trigger aberrant immune responses. A comprehensive understanding of the innate immune mechanisms involved in MAFLD/NAFLD/NASH pathophysiology will help the discovery of early interventions to prevent the disease, and lead to potential innovative therapeutic strategies that may limit its worldwide burden.

Keywords: Innate immune response; liver fibrosis; metabolic syndrome; metabolic-associated fatty liver disease; nonalcoholic fatty liver disease.

Figure 1

Innate immune modulation in MAFLD/NAFLD pathophysiology. Early reshaping of the innate immune signaling during MAFLD/NAFLD initiates an inflammatory cascade, resulting in uncontrolled liver injury and fibrogenesis. The hepatic repertoire of innate immune cells includes Kupffer cells, neutrophils, dendritic cells, hepatic stellate cells, innate immune-like resident T cells (including iNKT, γδT and MAIT cells), liver sinusoidal endothelial cells, mast cells, natural killer cells, platelets and hepatocytes that detect metabolic-associated stress signals (PAMPs, DAMPs) and elicit an immune response via the transcriptional regulation of proinflammatory mediators, including cytokines, chemokines, and cell growth factors. Adipose–liver organ crosstalk is mediated by the release of proinflammatory cytokines, chemokines, adipocytokines, miRNAs, extracellular vesicles and metabolites, promoting liver inflammation and injury. In addition, adipocyte transition during metabolic syndrome-associated events and nutrient-related signals (high-fat diet) triggers enhanced macrophage phenotypic differentiation that further aggravates disease progression. Intestinal bacterial dysbiosis drives inflammation and the production of metabolic by-products, such as ethanol and endotoxins/lipopolysaccharides, that in turn cause intestinal-mucosa barrier dysfunction and increased gut permeability. Thus, via the gut–liver axis (biliary system and the portal vein) the liver is exposed to flora metabolites and altered bile acids, promoting the development and progression of MAFLD/NAFLD AMPs, antimicrobial peptides; γδT, γδ Tcells; CCL-2, C-C motif chemokine -2; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; EGF, epidermal growth factor; ER, endoplasmic reticulum; FGF, fibroblast growth factor; HSCs, hepatic stellate cells; HGF, hepatocyte growth factor; IGF, insulin growth factor; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; iNKT, invariant natural killer T cell; KCs, Kupffer cells; LPS, lipopolysaccharides; LSECs, liver sinusoidal endothelial cells; MAFLD, metabolic (dysfunction)-associated fatty liver disease; MCP-1, monocyte chemoattractant protein-1; MMPs, matrix metalloproteases; MAIT cell, mucosal associated invariant T cell; MPO, myeloperoxidase; NK, natural killer cells; PMNs, neutrophils; NAFLD, nonalcoholic fatty liver disease; NETs, neutrophil extracellular traps; PAMPs, pathogen-associated molecular patterns; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; Th1, T helper 1; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; VCAM, vascular cell adhesion protein; VEGF, vascular endothelial growth factor; NE, norepinephrine