Non-alcoholic fatty liver disease (NAFLD) is considered to be one of the most frequent chronic liver diseases worldwide and is associated with an increased risk of developing liver cirrhosis and hepatocellular carcinoma. Hepatic macrophages, mainly comprising monocyte derived macrophages and tissue resident Kupffer cells, are characterized by a high diversity and plasticity and act as key regulators during NAFLD progression, in conjunction with other infiltrating myeloid cells like neutrophils or dendritic cells. The activation and polarization of myeloid immune cells is influenced by dietary components, inflammatory signals like danger-associated molecular patterns (DAMPs) or cytokines as well as gut-derived inflammatory factors such as pathogen-associated molecular patterns (PAMPs). The functionality of myeloid leukocytes in the liver is directly linked to their inflammatory polarization, which is shaped by local and systemic inflammatory mediators such as cytokines, chemokines, PAMPs, and DAMPs. These environmental signals provoke intracellular adaptations in myeloid cells, including inflammasome and transcription factor activation, inflammatory signaling pathways, or switches in cellular metabolism. Dietary changes and obesity also promote a dysbalance in intestinal microbiota, which can facilitate intestinal permeability and bacterial translocation. The aim of this review is to highlight recent findings on the activating pathways of innate immune cells during the progression of NAFLD, dissecting local hepatic and systemic signals, dietary and metabolic factors as well as pathways of the gut-liver axis. Understanding the mechanism by which plasticity of myeloid-derived leukocytes is related to metabolic changes and NAFLD progression may provide options for new therapeutic approaches.
Keywords: NASH; PAMPs; fibrosis; innate immunity; lipotoxicity; macrophages; metabolism; steatosis.