Hepatocyte-Derived IL-25 Promotes Macrophage Extracellular Trap Formation and Drives Liver Fibrosis Progression

Area of Science:

• Hepatology
• Immunology
• Cell Biology

Background:

• Liver fibrosis (LFib) is a progressive disease with significant health implications.
• Macrophage extracellular traps (METs) are implicated in LFib, but their triggers and mechanisms are unclear.
• Interleukin-25 (IL-25) influences macrophage metabolism and LFib progression.

Purpose of the Study:

• To investigate the role of IL-25 in triggering METs formation in LFib.
• To elucidate the mechanistic link between IL-25, METs, and hepatic stellate cell (HSC) activation.
• To identify IL-25 as a potential therapeutic target for LFib.

Main Methods:

• Established a carbon tetrachloride (CCl₄)-induced mouse model of LFib.
• Utilized in vitro co-culture systems and conditioned medium treatments.
• Generated hepatocyte-specific IL-25 conditional knockout (IL-25CKO) mice.
• Employed electron microscopy, immunofluorescence, Western blot, and ELISA for mechanistic studies.

Main Results:

• Early IL-25 co-localization with hepatocytes preceded METs formation in fibrotic livers.
• Hepatocyte-derived IL-25 acts as a trigger for METs formation.
• IL-25 stimulation induced METs formation via IL-17RB receptor activation, reactive oxygen species (ROS) bursts, and lysosomal activation.
• METs mediated the activation of hepatic stellate cells (HSCs) in vitro.

Conclusions:

• Identified a pathogenic axis involving hepatocytes, macrophages, and HSCs in LFib.
• Demonstrated that IL-25 is a key initiator of METs formation in LFib.
• Supports early IL-25 blockade as a promising therapeutic strategy for liver fibrosis.