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<p>Liver Fibrosis (LFib) represents a significant global health burden as a chronic progressive disease. Emerging evidence has established a critical link between macrophage extracellular traps (METs) and LFib; however, the precise triggers of METs formation and their mechanistic contributions to fibrosis remain poorly understood. Substantial evidence indicates that interleukin-25 (IL-25) potently regulates macrophage metabolism and LFib progression. A carbon tetrachloride (CCl₄)-induced mouse model of liver fibrosis spanning distinct stages (2 to 8&#xa0;weeks) was established. In vitro studies utilized co-culture systems and conditioned medium treatment to assess METs-mediated activation of hepatic stellate cells (HSCs). To elucidate the specific role of IL-25, hepatocyte-specific IL-25 conditional knockout (IL-25CKO) mice were generated using CRISPR/Cas9 technology and subjected to the LFib model. Mechanistic investigations involved stimulating RAW 264.7 macrophages with rmIl-25 and specific inhibitors. Techniques such as scanning/transmission electron microscopy, immunofluorescence, Western blot and ELISA were employed to analyze MET formation, ROS production, lysosomal activation, mitophagy, and related signaling pathways. Fibrotic livers exhibited strong early co-localization of IL-25 with hepatocytes, which preceded METs formation. This demonstrates that early production of IL-25 by hepatocytes acts as a triggering factor for METs formation. In vitro co-culture systems revealed METs-mediated activation of HSCs, while mechanistic studies showed that IL-25 promotes IL-17RB receptor activation, triggering downstream reactive oxygen species (ROS) bursts, lysosomal activation, and METs formation. This work identifies a pathogenic hepatocyte–macrophage–HSC axis and supports IL-25 early blockade as a promising clinical strategy for LFib.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Cheng-Jiang Cao,
  • Ming Yang,
  • Chang-Lin Du,
  • Xue Fang,
  • He-Hang Song,
  • Wen-Jing Wang,
  • Miao-Miao Wang,
  • Wen-Mei Zhang,
  • Zhen-Long Liu,
  • Cheng Huang,
  • Jun Li

摘要

Liver Fibrosis (LFib) represents a significant global health burden as a chronic progressive disease. Emerging evidence has established a critical link between macrophage extracellular traps (METs) and LFib; however, the precise triggers of METs formation and their mechanistic contributions to fibrosis remain poorly understood. Substantial evidence indicates that interleukin-25 (IL-25) potently regulates macrophage metabolism and LFib progression. A carbon tetrachloride (CCl₄)-induced mouse model of liver fibrosis spanning distinct stages (2 to 8 weeks) was established. In vitro studies utilized co-culture systems and conditioned medium treatment to assess METs-mediated activation of hepatic stellate cells (HSCs). To elucidate the specific role of IL-25, hepatocyte-specific IL-25 conditional knockout (IL-25CKO) mice were generated using CRISPR/Cas9 technology and subjected to the LFib model. Mechanistic investigations involved stimulating RAW 264.7 macrophages with rmIl-25 and specific inhibitors. Techniques such as scanning/transmission electron microscopy, immunofluorescence, Western blot and ELISA were employed to analyze MET formation, ROS production, lysosomal activation, mitophagy, and related signaling pathways. Fibrotic livers exhibited strong early co-localization of IL-25 with hepatocytes, which preceded METs formation. This demonstrates that early production of IL-25 by hepatocytes acts as a triggering factor for METs formation. In vitro co-culture systems revealed METs-mediated activation of HSCs, while mechanistic studies showed that IL-25 promotes IL-17RB receptor activation, triggering downstream reactive oxygen species (ROS) bursts, lysosomal activation, and METs formation. This work identifies a pathogenic hepatocyte–macrophage–HSC axis and supports IL-25 early blockade as a promising clinical strategy for LFib.