Clinical implications of inflammation in steatotic liver disease: Heterogeneity of neutrophils in tissue injury and host defense

Steatotic liver disease is the most common form of liver disease induced by the metabolic syndrome, excessive alcohol use, or their combination. In progression of steatohepatitis to liver fibrosis, sustained inflammation and activation of innate immune cells plays a critical role. Neutrophils play a critical role in sustaining inflammation as well as in host defense. In this study, we identified neutrophil populations with activated or exhausted phenotypes in alcohol-associated steatohepatitis and discovered induction of neutrophil extracellular traps (NETs) by alcohol in the setting of metabolic dysfunction-associated steatohepatitis (MASH). Mechanistically, we describe how the NLRP3 inflammasome and NLRP3-IL-ß axis is a key component in sustained liver inflammation in MASH, alcohol-induced steatohepatitis, and their combined insult. Finally, using preclinical models, we demonstrate that targeting neutrophils, disruption of NETs, or NLRP3 inflammasome activation are promising directions for new therapeutic approaches in steatohepatitis. Abbreviations: MASH, metabolic dysfunction-associated steatohepatitis; AH, alcohol-associated hepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; ALD, alcohol-associated liver disease; MetALD, metabolic syndrome and alcohol-associated liver disease; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; NLRP3, nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3; DAMPs, damage-associated molecular patterns; PAMPS, pathogen-associated molecular patterns; NETs, neutrophil extracellular traps.