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

作者：Cheng-Jiang Cao, Min Yang, Changlin Du, Xue Fang, He-Hang Song, Wen-Jing Wang, Miao-Miao Wang, Wenmei Zhang, Zhen-Long Liu, Cheng Huang, Jun Li · 发表于：Inflammation · 年份：2026 · DOI：10.1007/s10753-026-02506-6 · 被引用次数：1 · 研究领域：Liver physiology and pathology、Immune cells in cancer、Cytokine Signaling Pathways and Interactions

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...