GZMA suppressed GPX4-mediated ferroptosis to improve intestinal mucosal barrier function in inflammatory bowel disease

作者：Rongwei Niu, Jiaoli Lan, Danxia Liang, Xiang Li, Jiaxin Wu, Xiaoyan Zhang, Zhi‐Ling Li, Huan Chen, Lanlan Geng, Wanfu Xu, Sitang Gong, Min Yang · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01836-y · 被引用次数：19 · 研究领域：Cancer-related molecular mechanisms research、Ferroptosis and cancer prognosis、MicroRNA in disease regulation

BACKGROUND: T cells, enrichment of granzyme A (GZMA), was found in pediatric-onset colitis and inflammatory bowel disease (IBD) characterized by impaired intestinal barrier function. However, the influence of GZMA on intestinal barrier function remains unknown. METHODS: Western blotting(WB), real-time PCR (qPCR), immunofluorescence (IF) and in vitro permeability assay combined with intestinal organoid culture were used to detect the effect of GZMA on intestinal epithelial barrier function in vivo and in vitro. Luciferase, immunoprecipitation (IP) and subcellular fractionation isolation were performed to identify the mechanism through which GZMA modulated intestinal epithelial barrier function. RESULTS: T cells promoted intestinal epithelial barrier function through GZMA, leading to induce Occludin(OCLN) and Zonula Occludens-1(ZO-1) expression, which was attributed to enhanced CDX2-mediated cell differentiation caused by increased glutathione peroxidase 4(GPX4)-induced ferroptosis inhibition in vivo and in vitro. Mechanically, GZMA inhibited intestinal epithelial cellular PDE4B activation to trigger cAMP/PKA/CREB cascade signaling to increase CREB nuclear translocation, initiating GPX4 transactivity. In addition, endogenous PKA interacted with CREB, and this interaction was enhanced in response to GZMA. Most importantly, administration of GZMA could alleviate DSS-induced colitis in vivo. CONCLUSION: These findings extended the novel insight of GZMA contributed to intestinal ep...