Dual role of neutrophils in modulating liver injury and fibrosis during development and resolution of diet-induced murine steatohepatitis.

Abstract

Inflammatory changes in the liver represent a key feature of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD). Innate immune activation including hepatic neutrophilic infiltration acts as an important inflammatory trigger as well as a potential mediator of inflammation resolution. In this study, we dissected the effects of neutrophil depletion via anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibodies administration during ongoing high fat-fructose-cholesterol (FFC) diet-induced murine NASH and during inflammation resolution by switching into a low-fat control diet. During NASH progression, protective effects were shown as HSC activation, cell infiltration and activation of pro-inflammatory macrophages were ameliorated. Furthermore, these changes were contrasted with the effects observed when neutrophil depletion was performed during the resolution phase. Impaired resolving mechanisms, such as a failure to balance the pro and anti-inflammatory cytokines ratio, deficient macrophage phenotypic switch into a pro-restorative profile, and defective repair and remodeling processes were observed when neutrophils were depleted in this scenario. This study described phase-dependent contrasting roles of neutrophils as triggers and pro-resolutive mediators of liver injury and fibrosis associated with diet-induced NASH in mice. These findings have important translational implications at the time of designing NASH therapeutic strategies.

• Authors: Andrea D Kim, Sung Eun Kim, Aleksandra Leszczynska, Benedikt Kaufmann, Agustina Reca, Dong Joon Kim, Ariel E Feldstein
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 24194 (12 17 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34921208 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s).

Chemical References

• Cytokines
• Fructose
• Hydroxyproline

Topics

• Animals
• Cytokines (metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Fructose (metabolism)
• Hydroxyproline (metabolism)
• Liver
• Liver Cirrhosis (metabolism)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophils (metabolism)
• Non-alcoholic Fatty Liver Disease (metabolism)