Decoding the CHI3L1/IL-13Rα2 signaling nexus in MASH-fibrosis pathogenesis

Area of Science:

• Hepatology
• Immunology
• Fibrosis Research

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by inflammation and fibrosis.
• The precise immune mechanisms driving MASH pathogenesis remain incompletely understood.

Purpose of the Study:

• To elucidate the immune mechanisms linking inflammation and fibrosis in MASH.
• To identify key molecular mediators and signaling pathways involved in MASH progression.
• To evaluate CHI3L1 as a potential therapeutic target for MASH-associated liver fibrosis.

Main Methods:

• Hepatocyte-macrophage co-culture assays and recombinant interleukin-17A (IL-17A) stimulation.
• Investigation of signaling pathways including JNK/c-Jun and p38 MAPK/ATF3.
• Utilized cell-specific knockout mouse models for Chi3l1 and Il13ra2.
• Employed CHI3L1-neutralizing antibodies in preclinical models.

Main Results:

• Identified a hepatocyte-derived IL-17A signal that enhances macrophage CHI3L1 expression via JNK/c-Jun.
• Demonstrated that CHI3L1 binds IL-13Rα2 on hepatic stellate cells (HSCs), activating p38 MAPK/ATF3.
• Showed that this cascade induces lipocalin-2 (LCN2), promoting HSC activation and liver fibrosis.
• Deletion of Chi3l1 or Il13ra2 significantly reduced liver inflammation and fibrosis.
• CHI3L1 neutralization improved MASH disease outcomes in mice.

Conclusions:

• Uncovered a novel IL-17A-CHI3L1-IL-13Rα2-LCN2 signaling axis in MASH pathogenesis.
• Established CHI3L1 as a critical mediator connecting immune activation to fibrotic remodeling in MASH.
• Positioned CHI3L1 as a promising therapeutic target for mitigating MASH-associated liver fibrosis.