The following is a summary of the “Neutrophil extracellular traps contribute to liver damage and increase defective low-density neutrophils in alcohol-associated hepatitis,” published in the January 2023 issue of Hepatology by Cho, et al.
Inflammation and neutrophil counts are linked to poor clinical outcomes in alcoholic hepatitis (AH). This study aimed to examine the role of neutrophils in AH-related liver injury. Neutrophil extracellular traps (NETs) were the focus of our study, and we used RNA sequencing to delve deeper into the distinct properties of AH-related neutrophils.
In AH, they found that NET production had dramatically increased. They also found that people with AH and alcohol-fed have a different low-density neutrophil (LDN) population than healthy controls. An investigation of the transcriptomes of low-density neutrophils (LDNs) and high-density neutrophils (HDNs) from the periphery of people with AH showed that LDNs have a functionally fatigued phenotype, whereas HDNs are active.
The reactive oxygen species (ROS) generation of AH HDNs was higher at rest and increased in response to lipopolysaccharide than that of control HDNs, whereas AH LDNs did not respond to lipopolysaccharide. We demonstrate that LDNs are derived from HDNs following in vitro alcohol-induced NET release and that this LDN subset has impaired functioning, including lower phagocytic capacity. Dysfunctional neutrophils may persist in the bloodstream and the liver because LDNs have a diminished homing capacity and are less likely to be cleared by macrophage efferocytosis.
Alcohol-induced NET synthesis and liver damage were avoided by depleting both HDNs and LDNs in vivo. They were treated with granulocyte-colony stimulating factors and saw reduced liver damage brought on by alcohol. Increased NET production by neutrophils is a factor in developing more faulty LDNs in AH, contributing to liver damage. Alcohol alters neutrophil phenotypes, stimulating HDNs while inhibiting LDNs. The molecular insights provided by our research could help design treatment strategies for AH.