IL-25 Improves MAFLD by Suppressing the Notch Signalling in Hepatic Macrophages

Area of Science:

• Hepatology
• Immunology
• Molecular Biology

Background:

• Metabolic dysfunction-associated fatty liver disease (MAFLD) involves lipid accumulation, inflammation, and fibrosis.
• Macrophage polarization is critical in MAFLD progression.

Purpose of the Study:

• Investigate interleukin-25 (IL-25)'s role in modulating macrophage polarization and Notch signaling in a methionine-choline-deficient (MCD) diet-induced MAFLD model.

Main Methods:

• Utilized a methionine-choline-deficient (MCD) diet model in C57BL/6 mice to induce MAFLD.
• Employed RT-qPCR, ELISA, Western blot, immunofluorescence, ChIP, and luciferase assays on mouse livers, human hepatocytes, and primary hepatic macrophages.
• Assessed gene and protein expression, and analyzed STAT3/Notch-1 signaling pathways.

Main Results:

• IL-25 expression was downregulated in MAFLD livers and palmitic acid-treated hepatocytes.
• IL-25 treatment induced M2 macrophage polarization (increased Arg1, Chi3l3, IL-10, TGF-β) and suppressed M1 polarization (decreased TNF-α, IL-6).
• IL-25 inhibited STAT3/Notch-1, induced IL-33, and negatively regulated NF-κB/Jagged-1, ameliorating hepatic steatosis and ductular reaction.

Conclusions:

• IL-25 modulates macrophage polarization and inflammation in MAFLD.
• IL-25 shows potential as a therapeutic strategy for inflammatory liver diseases.