Mucosal Immunol. 2025 Jun 4:S1933-0219(25)00056-X. doi: 10.1016/j.mucimm.2025.05.008. Online ahead of print.
ABSTRACT
Intestinal fibrosis is one of the most threatening complications of Crohn’s disease (CD). Although our previous study identified the profibrotic role of amphiregulin (AREG) in intestinal fibrosis, the underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanisms by which AREG mediates intestinal fibrosis. Specimens from stenotic and non-stenotic lesions in CD patients were collected, alongside normal specimens from individuals with intestinal diverticula, for the assessment of AREG levels. A dextran sulfate sodium (DSS)-induced chronic colitis model was established in wild type (WT) and Areg-knockout (Areg-/-) mice. RNA-sequencing (RNA-seq) was performed on human intestinal fibroblasts (HIFs) to elucidate the underlying mechanisms. Additionally, the single-cell RNA-seq data of full-thickness CD, obtained from Prof. Rieder, was reanalyzed. Elevated levels of AREG were detected at stenotic sites in patients with CD. Areg-/- colitis mice exhibited decreased intestinal fibrosis. AREG enhanced the activation and proliferation of HIFs by activating the PI3K/AKT pathway. The inhibitor of the PI3K/AKT pathway effectively suppressed AREG-induced activation and proliferation of HIFs and attenuated colitis-associated fibrosis in mice. In stricturing CD, inflammatory monocytes exhibited higher AREG levels, contributing to the activation and proliferation of intestinal fibroblasts. Adoptive transfer of Ly6chi inflammatory monocytes from WT but not Areg-/- mice exacerbated intestinal fibrosis in DSS-induced colitis mice. These findings reveal that inflammatory monocytes derived-AREG promotes intestinal fibrosis in experimental colitis and CD patients by promoting intestinal fibroblasts activation and proliferation through the PI3K/AKT pathway. Inflammatory monocytes serve as the primary source of AREG in stricturing CD, critically mediating fibroblast-related fibrotic progression in an AREG-dependent manner. Therefore, AREG, the PI3K/AKT pathway and inflammatory monocytes may serve as potential therapeutic targets for intestinal fibrosis in CD.
PMID:40480418 | DOI:10.1016/j.mucimm.2025.05.008