Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China.
Department of Pediatrics, Shantou Central Hospital, Shantou, 515031, China.
J Mol Med (Berl). 2024 Oct;102(10):1199-1215. doi: 10.1007/s00109-024-02477-x. Epub 2024 Aug 13.
Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B high‑expressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B high‑expressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B high‑expressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B high‑expressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/β-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/β-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B high‑expressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/β-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.
纤维化是炎症性肠病（IBD）的重要病理变化，但发病机制尚未阐明。WNT2B 高表达的成纤维细胞在 IBD 肠道组织中富集，尽管这组成纤维细胞的确切功能仍不清楚。本研究探讨了 WNT2B 高表达的成纤维细胞是否加重了肠道组织损伤和纤维化。我们的研究提供了证据，表明 WNT2B 高表达的成纤维细胞和 NK 细胞在 IBD 患者的结肠炎组织中富集。WNT2B 高表达的成纤维细胞分泌 wnt2b，与 NK 细胞上的 FZD4 结合，激活 NF-κB 和 STAT3 通路，增强 IL-33 的表达。WNT/β-catenin 通路的下游成分 TCF4 与 p65 结合，促进与 IL-33 启动子的结合。此外，WNT/β-catenin 通路抑制剂 Salinomycin 抑制结肠炎中 IL-33 的分泌，从而减轻肠道炎症。敲低 WNT2B 可减少结肠炎中 NK 细胞的浸润和 IL-33 的分泌，减少肠道炎症和纤维化。总之，WNT2B 高表达的成纤维细胞通过分泌 wnt2b 激活 NK 细胞，激活 WNT/β-catenin 和 NF-κB 通路，促进 IL-33 的表达和分泌，从而导致 IBD 结肠纤维化的诱导。关键信息：WNT2B 高表达的成纤维细胞和 NK 细胞在结肠炎组织中富集，促进 NK 细胞分泌 IL-33。Wnt2b 通过激活 p65 而不是 STAT3 激活 NF-κB 和 STAT3 通路促进 IL-33 的表达。TCF4 与 p65 结合并上调 NF-κB 通路。Salinomycin 减少结肠炎中 NK 细胞的浸润和 IL-33 的分泌。敲低 WNT2B 可减轻慢性结肠炎中的炎症和纤维化。
