Abstract：
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.
摘要：
纤维化是炎症性肠病(IBD)的重要病理改变,但是机制尚未阐明。WNT2B高表达成纤维细胞在IBD肠组织中富集，尽管该组成纤维细胞的确切功能尚不清楚。这项研究调查了WNT2B高表达的成纤维细胞是否会加重肠组织损伤和纤维化。我们的研究提供了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的证据。WNT2B高表达成纤维细胞分泌wnt2b，它与NK细胞上的FZD4结合并激活NF-κB和STAT3途径以增强IL-33的表达。TCF4，WNT/β-catenin通路的下游成分，与p65结合并促进与IL-33启动子的结合。此外，沙利霉素,WNT/β-连环蛋白途径的抑制剂，抑制结肠炎中IL-33的分泌，从而减少肠道炎症。敲除WNT2B可减少结肠炎中NK细胞浸润和IL-33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，可能导致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激活NF-κB，STAT3途径通过激活p65而不是STAT3促进IL-33表达。综合征TCF4与p65结合并上调NF-κB通路。盐霉素减少结肠炎中NK细胞浸润和IL-33分泌。敲除WNT2B减轻慢性结肠炎的炎症和纤维化。
