谷胱甘肽s-转移酶α 4失活可通过促进巨噬细胞铁凋亡来阻断粪肠球菌诱导的旁观者效应。

IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut Microbes Pub Date : 2025-12-01 Epub Date: 2025-01-16 DOI:10.1080/19490976.2025.2451090
Yuanyuan Ju, Chunhua Ma, Lin Huang, Yumei Tao, Tianqi Li, Haibo Li, Mark M Huycke, Yonghong Yang, Xingmin Wang
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引用次数: 0

摘要

粪肠球菌感染的巨噬细胞产生4-羟基壬烯醛(4-HNE),介导微生物诱导的旁观者效应(MIBE),导致结直肠癌(CRC)。谷胱甘肽s-转移酶α 4 (Gsta4)是一种特异性的4- hne解毒酶,在人类结直肠癌和粪肠杆菌诱导的小鼠结直肠癌中过表达。然而,Gsta4在粪肠杆菌诱导的结肠炎和结直肠癌中的作用尚不清楚。在此,我们证明Gsta4通过保护巨噬细胞免受粪肠杆菌诱导的铁凋亡而对MIBE至关重要。采用粪肠杆菌OG1RFSS灌胃诱导Gsta4-/-和Il10-/-/Gsta4-/-小鼠结肠炎。在gsta4缺失的小鼠巨噬细胞中评估了铁下垂。我们发现,与Il10-/-小鼠不同,被粪肠杆菌定植的Gsta4-/-和Il10-/-/Gsta4-/-小鼠没有发生结肠炎或结直肠癌。免疫荧光染色显示粪肠杆菌定殖的il - 10-/-/Gsta4-/-小鼠固有层巨噬细胞减少,Gpx4表达降低,提示铁下沉发生。在感染粪肠杆菌的gsta4缺陷小鼠巨噬细胞中进一步证实了铁下垂。此外,Gsta4失活诱导Hmox1上调和c-Jun磷酸化,同时阻断Nos2表达,导致细胞内亚铁铁积累,脂质过氧化,最终导致铁死亡。最后,Mapk8作为铁下垂驱动因子,在E. faecalis感染的gsta4缺陷巨噬细胞中显著升高。这些结果表明Gsta4失活通过消除巨噬细胞来阻断MIBE,从而减轻粪肠杆菌诱导的结肠炎和CRC。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis.

Enterococcus faecalis-infected macrophages produce 4-hydroxynonenal (4-HNE) that mediates microbiota-induced bystander effect (MIBE) leading to colorectal cancer (CRC). Glutathione S-transferase alpha 4 (Gsta4), a specific detoxifying enzyme for 4-HNE, is overexpressed in human CRC and E. faecalis-induced murine CRC. However, the roles of Gsta4 in E. faecalis-induced colitis and CRC remain unclear. Herein, we demonstrate that Gsta4 is essential for MIBE by protecting macrophages from E. faecalis-induced ferroptosis. E. faecalis OG1RFSS was used to induce colitis in Gsta4-/- and Il10-/-/Gsta4-/- mice by orogastric gavage. Ferroptosis was assessed in Gsta4-deficient murine macrophages. We found that, unlike Il10-/- mice, Gsta4-/- and Il10-/-/Gsta4-/- mice colonized with E. faecalis failed to develop colitis or CRC. Immunofluorescent staining showed a reduction of macrophages in the lamina propria of E. faecalis-colonized Il10-/-/Gsta4-/- mice, as well as decreased Gpx4 expression, indicating the occurrence of ferroptosis. Ferroptosis was further confirmed in Gsta4-deficient murine macrophages infected with E. faecalis. Moreover, Gsta4 inactivation induced the upregulation of Hmox1 and phosphorylated c-Jun while blocked Nos2 expression, leading to the accumulation of intracellular ferrous iron, lipid peroxidation and, eventually, ferroptosis. Finally, Mapk8, as a ferroptosis driver, was remarkably elevated in E. faecalis-infected Gsta4-deficient macrophages. These results suggest that Gsta4 inactivation blocks MIBE by eliminating macrophages, thereby attenuates E. faecalis-induced colitis and CRC.

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来源期刊
Gut Microbes
Gut Microbes Medicine-Microbiology (medical)
CiteScore
18.20
自引率
3.30%
发文量
196
审稿时长
10 weeks
期刊介绍: The intestinal microbiota plays a crucial role in human physiology, influencing various aspects of health and disease such as nutrition, obesity, brain function, allergic responses, immunity, inflammatory bowel disease, irritable bowel syndrome, cancer development, cardiac disease, liver disease, and more. Gut Microbes serves as a platform for showcasing and discussing state-of-the-art research related to the microorganisms present in the intestine. The journal emphasizes mechanistic and cause-and-effect studies. Additionally, it has a counterpart, Gut Microbes Reports, which places a greater focus on emerging topics and comparative and incremental studies.
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