A Protein Complex of Liver Origin Activates a Pro-inflammatory Program That Drives Hepatic and Intestinal Injury in...

Area of Science:

• Hepatology
• Immunology
• Gastroenterology

Background:

• Alcohol-associated liver disease (AALD) pathogenesis involves the liver-to-gut axis.
• Oxidized high-mobility group box-1 ([O] HMGB1) is elevated in alcoholic patients.
• Interleukin-1 beta (IL-1B) is increased in AALD, suggesting a role in disease progression.

Purpose of the Study:

• To investigate the role of hepatocyte-derived [O] HMGB1 in AALD.
• To determine if [O] HMGB1 interacts with IL-1B to promote inflammation and intestinal barrier dysfunction.

Main Methods:

• Utilized alcohol-fed Rage^ΔMye mice models.
• Analyzed hepatic and intestinal inflammation, permeability, and lipopolysaccharide levels.
• Investigated the formation and function of an [O] HMGB1-IL-1B complex in liver and gut.

Main Results:

• Alcohol-fed Rage^ΔMye mice showed reduced inflammation and intestinal permeability, indicating protection from AALD.
• [O] HMGB1 signals through RAGE in myeloid cells, exacerbating hepatic inflammation and gut barrier dysfunction.
• A liver-originating [O] HMGB1-IL-1B complex activates RAGE in Kupffer cells, macrophages, and intestinal cells, driving inflammation and permeability.

Conclusions:

• A novel liver-derived protein complex of [O] HMGB1 and IL-1B amplifies the pro-inflammatory feedback loop in AALD.
• This complex contributes to both liver damage and intestinal barrier dysfunction.
• Targeting this complex presents a potential therapeutic strategy for AALD.