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

IF 8.2 2区 生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-10-04 DOI:10.1186/s12964-024-01836-y
Rongwei Niu, Jiaoli Lan, Danxia Liang, Li Xiang, Jiaxin Wu, Xiaoyan Zhang, Zhiling Li, Huan Chen, Lanlan Geng, Wanfu Xu, Sitang Gong, Min Yang
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Abstract

Background: Our previous study has demonstrated a decreased colonic CD8+CD39+ 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: Herein, we, for the first time, demonstrated that CD8+CD39+ 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 epithelial cell differentiation to improve barrier function, and enhacement of GZMA could be a promising strategy to patients with IBD.

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GZMA 可抑制 GPX4 介导的铁蛋白沉积,从而改善炎症性肠病的肠粘膜屏障功能。
背景:我们之前的研究表明,在小儿结肠炎和炎症性肠病(IBD)中发现结肠 CD8+CD39+ T 细胞减少,颗粒酶 A(GZMA)富集,其特征是肠屏障功能受损。然而,GZMA 对肠屏障功能的影响仍然未知:方法:采用 Western 印迹(WB)、实时 PCR(qPCR)、免疫荧光(IF)和体外渗透性试验结合肠道类器官培养,检测 GZMA 在体内和体外对肠上皮屏障功能的影响。通过荧光素酶、免疫沉淀(IP)和亚细胞分馏分离,确定了GZMA调节肠上皮屏障功能的机制:结果:我们首次证明CD8+CD39+ T细胞通过GZMA促进肠上皮屏障功能,导致诱导Occludin(OCLN)和Zonula Occludens-1(ZO-1)的表达,这归因于体内和体外谷胱甘肽过氧化物酶4(GPX4)诱导的铁变态反应抑制增加导致CDX2介导的细胞分化增强。从机制上讲,GZMA 可抑制肠上皮细胞 PDE4B 的活化,从而触发 cAMP/PKA/CREB 级联信号,增加 CREB 核转位,启动 GPX4 的转录。此外,内源性 PKA 与 CREB 相互作用,这种相互作用在 GZMA 的作用下得到加强。最重要的是,服用GZMA可以缓解DSS诱导的体内结肠炎:这些发现扩展了GZMA有助于肠上皮细胞分化以改善屏障功能的新见解,增强GZMA可能是治疗IBD患者的一种有前途的策略。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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