Work

IL-33/ST2 signaling promotes intrahepatic cholangiocarcinoma through reprogramming macrophage polarization via MAPK pathway

Year: 2025

Type: article

Abstract: BACKGROUND: The role of IL-33/ST2 signaling in reprogramming macrophage polarization within the intrahepatic cholangiocarcinoma (ICC) microenvironment remains poorly understood. This study aimed to elucidate the mechanisms by which IL-33/ST2 signaling regulates macrophage polarization and its impact on ICC progression. METHODS: we overexpressed IL-33 in mouse macrophage J774A.1 cells and blocked IL-33/ST2 signaling using a ST2-neutralizing antibody. These macrophages were co-cultured with human ICC cells (HuCCT1 and RBE). Subcutaneous and orthotopic xenograft mouse models of ICC were established to assess the effects of ST2 blockade and adoptive transfer of differentially treated macrophages. RESULTS: IL-33 overexpression in J774A.1 cells significantly increased M2 macrophage marker expression, which was reversed by ST2 neutralization. This was associated with enhanced phosphorylation of ERK1, JNK, and P38, indicating MAPK pathway activation. Co-culture with IL-33-overexpressing macrophages promoted the invasion, migration and epithelial-mesenchymal transition (EMT) of ICC cells, effects that were attenuated by ST2 blockade. In vivo, ST2-neutralizing antibody inhibited ICC tumor growth, while infusion of M2 macrophages promoted it. Xenograft tumor tissues showed elevated expression of IL-33, ST2, M2 markers, and phosphorylated MAPK proteins, which were reduced upon ST2 neutralization. CONCLUSION: IL-33/ST2 signaling drives ICC progression by promoting M2 macrophage polarization via the MAPK pathway. Targeting this axis may represent a novel therapeutic strategy for ICC.

Source: Experimental Cell Research

DOI: 10.1016/j.yexcr.2025.114845