Figure 1.

Role of neutrophils in the development of NASH. Metabolic syndrome is often associated with excessive lipid accumulation in the liver. Under these conditions, the probability of hepatocytes being exposed to lipotoxic lipid species, such as fatty acids, ceramides, cholesterol, and sphingolipids, is high. Lipotoxic hepatocytes release neutrophil-recruiting chemokines, including CXCL1 and IL-8. Infiltrating neutrophils exert various actions that facilitate NASH development. Activated neutrophils produce ROS via an oxidative burst that involves the activity of enzymes, such as NADPH oxidase 2. ROS may directly cause hepatocyte injury. ROS also activate and recruit macrophages, which further enhance hepatocyte injury and inflammation by releasing inflammatory cytokines. Cytokines released by macrophages (e.g., transforming growth factor-β) activate hepatic stellate cells (HSCs) and promote fibrosis. Neutrophil-derived ROS also contribute to HSC activation. Neutrophil granule proteins, such as LCN2, MPO, and NE, have increasingly been recognized to contribute to sterile inflammation, although the exact mechanisms through which they contribute to NASH are unclear. NETs mediate inflammation during NASH development through mechanisms that are not yet fully understood. Neutrophil-derived factors such as ROS and granule proteins (e.g., MPO and NE) contribute to NET formation. Hepatocyte injury, inflammation, and fibrosis are the three hallmarks of NASH. MetS, metabolic syndrome; InsR, insulin resistance.