γ -分泌酶复合物的药理抑制剂破坏上皮细胞功能,引发小鼠结肠炎。

IF 8.7
Lena Erkert, Melanie Kabisch, Reyes Gamez-Belmonte, Miguel Gonzalez-Acera, Jay V Patankar, Lena Schödel, Katharina Hofmann, Yara Wagner, Christina Plattner, Eva-Maria Spath, Ute Distler, Stefan Tenzer, Clemens Neufert, Markus F Neurath, Christoph Becker
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引用次数: 0

摘要

背景与目的:抑制γ-分泌酶介导的Notch信号传导已被探索作为治疗阿尔茨海默病和癌症的潜在方法。然而,临床试验表明,这种方法可能会导致副作用,比如肠道炎症。Notch信号已被证明是肠上皮稳态的关键介质。我们的目的是研究γ-分泌酶抑制相关性结肠炎的分子机制。方法:用γ-分泌酶抑制剂处理小鼠和小肠类器官,采用不同的分子和组织学方法,以及转录组学和蛋白质组学分析,分析IEC分化和炎症相关标志物。为了评估微生物组在结肠炎发展中的作用,对γ-分泌酶药理学抑制的小鼠进行抗生素治疗。此外,对炎症性肠病(IBD)患者样本和对照样本进行分析,以评估Notch信号通路组分在IECs中的表达。结果:本研究表明,药理γ-分泌酶抑制可诱导小鼠小肠和大肠炎症,这种表型可在微生物群耗尽后恢复。抑制γ-分泌酶诱导上皮结构破坏和炎性细胞因子释放。在分子水平上,上皮类器官表现出与Notch信号缺陷相关的IEC分化中断和增殖受损。最后,对IBD患者的分析显示IECs中Notch通路成分的失调。结论:综上所述,全身使用γ-分泌酶抑制剂可通过损害小鼠IEC分化和引发肠道炎症来破坏上皮细胞功能。在设计涉及γ-分泌酶抑制剂的未来治疗干预措施时,应考虑这些发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacological inhibitors of the gamma-secretase enzyme complex disrupt epithelial cell function triggering colitis in mice.

Background and aims: Inhibiting γ-secretase-mediated Notch signaling has been explored as a potential treatment for Alzheimer's disease and cancer. However, clinical trials have revealed that this approach can lead to side effects, such as gut inflammation. Notch signaling has been shown to be a key mediator of intestinal epithelial homeostasis. We aimed to investigate the molecular mechanisms of γ-secretase inhibition-associated colitis.

Methods: Mice and small intestinal organoids were treated with γ-secretase inhibitors and analyzed for intestinal epithelial cell (IEC) differentiation and inflammation-associated markers using different molecular and histological approaches, along with transcriptomic and proteomic analyses. To evaluate the role of the microbiome in colitis development, mice undergoing pharmacological γ-secretase inhibition were treated with antibiotics. Additionally, inflammatory bowel disease (IBD) patient samples and control samples were analyzed to assess the expression of Notch signaling pathway components in IECs.

Results: This study shows that pharmacological γ-secretase inhibition induces inflammation in both the small and large intestine of mice, a phenotype that could be rescued upon microbiota depletion. Inhibiting the γ-secretase induced structural disruption of the epithelium and inflammatory cytokine release. On a molecular level, epithelial organoids exhibited disrupted IEC differentiation and impaired proliferation, associated with defective Notch signaling. Finally, analysis of IBD patients revealed deregulation of Notch pathway components within IECs.

Conclusions: In conclusion, systemic use of γ-secretase inhibitors disrupts epithelial cell function by impairing IEC differentiation and triggering gut inflammation in mice. These findings should be considered when designing future therapeutic interventions involving γ-secretase inhibitors.

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