The role of neutrophils in innate immunity-driven nonalcoholic steatohepatitis: lessons learned and future promise

The enrichment of innate immune cells and the enhanced inflammation represent the hallmark of non-alcoholic steatohepatitis (NASH), the advanced subtype with a significantly increased risk of progression to end-stage liver diseases within the spectrum of non-alcoholic fatty liver disease. Neutrophils are traditionally recognized as key components in the innate immune system to defend against pathogens. Recently, a growing body of evidence supports neutrophils as emerging key player in mediating the transition from steatosis to NASH, which is largely inspired by the histological findings in human liver biopsy indicating the enhanced infiltration of neutrophils as one of the key histological features of NASH. In this review, we discuss data regarding histological perspectives of hepatic infiltration of neutrophils in NASH. We also highlight the pathophysiological role of neutrophils in promoting metabolic inflammation in the liver through the release of a vast array of granule proteins, the interaction with other pro-inflammatory immune cells, and the formation of neutrophil extracellular traps. Neutrophil granule proteins possess pleiotropic effects on regulating neutrophil biology and functions. A variety of granule proteins (including lipocalin-2, myeloperoxidase, proteinase 3, neutrophil elastase, etc.) produced by neutrophils enhance liver metabolic inflammation, thereby promoting NASH progression by mediating neutrophil-macrophage interaction. Therapeutically, pharmacological inhibitors targeting neutrophil granule proteins hold promise to combat NASH. In addition, this article also summarizes potentials of neutrophils and its derived various granule proteins for the accurate, even non-invasive diagnosis of NASH. Graphic abstract