Neutrophil serine proteases NE and PR3 controlled by the miR-223/STAT3 axis potentiate MASH and liver fibrosis

Area of Science:

• Hepatology
• Immunology
• Molecular Biology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis pose significant health challenges with limited treatments.
• Neutrophil infiltration is observed in MASH, but the specific mediators driving disease progression are unclear.
• Neutrophil elastase (NE) and proteinase 3 (PR3) are implicated, but their precise roles in MASH and fibrosis require elucidation.

Purpose of the Study:

• To investigate the role of neutrophil elastase (NE) and proteinase 3 (PR3) in the pathogenesis of MASH and liver fibrosis.
• To explore the underlying mechanisms by which NE and PR3 contribute to MASH progression.

Main Methods:

• Analysis of liver biopsies from 121 morbidly obese patients with MASH and fibrosis.
• Induction of MASH and fibrosis in NE/PR3/microRNA-223 (miR-223) knockout mice and wild-type controls using a high-fat diet.
• Bone marrow transplantation experiments to assess miR-223 chimerism in hepatic cells.
• Genetic ablation and viral-mediated inhibition of NE and PR3 in mouse models.

Main Results:

• NE and PR3 levels were significantly elevated in human MASH liver biopsies, correlating with disease severity.
• Genetic deletion or inhibition of NE and PR3 markedly reduced MASH and liver fibrosis in mice.
• MiR-223 suppressed NE and PR3 by targeting STAT3; miR-223 deficiency exacerbated liver inflammation and fibrosis.
• Chimeric mice with altered miR-223 levels showed corresponding changes in hepatic NE/PR3 and MASH fibrosis progression.

Conclusions:

• Neutrophil elastase (NE) and proteinase 3 (PR3) are critical mediators of liver inflammation that promote MASH and fibrosis development.
• These findings highlight NE and PR3 as potential therapeutic targets for MASH and liver fibrosis.