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活性氧/半胱天冬酶-3/ Gasdermin E途径介导的焦亡在烟曲霉诱导的真菌性角膜炎中的作用

Pyroptosis Mediated by ROS/Caspase-3/GSDME Pathway in Aspergillus fumigatus-Induced Fungal Keratitis.

作者信息

Kan Jingze, Song Shiqi, Liu Mengzhu, Xu Qiang, Lee Jieun, Sun Jintao, Xue Shasha, Sun Xiaoyan, Che Chengye

机构信息

Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China.

Department of Ophthalmology, School of Medicine, Pusan National University, Yangsan, Korea.

出版信息

Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):52. doi: 10.1167/iovs.66.6.52.

DOI:10.1167/iovs.66.6.52
PMID:40525924
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12178440/
Abstract

PURPOSE

Gasdermin E (GSDME), cleaved by (casp-3) activation, is known as a key executor in pyroptosis. However, its role in fungal keratitis (FK) remains unclear. Thus we analyzed the role of GSDME, as well as its signaling pathway in Aspergillus fumigatus (AF)-induced FK.

METHODS

We conducted experiments using a mouse model and human corneal epithelial cells. Initially, we infected mice with AF at various time intervals and examined the progression of FK lesions, selecting the time point with the most severe lesions. Next, we pre-treated the subjects with various cytokine inhibitors that may influence pyroptosis. We then assessed the development of FK lesions and the production of inflammatory cytokines using qRT-PCR, flow cytometry, transmission electron microscopy, as well as Western blotting.

RESULTS

The optimal stimulation time for corneal epithelial cells in mice and humans was determined to be three days and 12 hours, respectively. In both the mouse and corneal epithelial cell models, GSDME significantly mediated AF-induced pyroptosis downstream of the reactive oxygen species (ROS)/casp-3/GSDME pathway and greatly influenced the inflammatory process and keratitis in AF-induced FK.

CONCLUSIONS

Overall, GSDME played a crucial role in pyroptosis during corneal inflammation. By modulating IL-1β release during pyroptosis, GSDME had a significant impact on the host immune response in FK. This process could be inhibited by blocking the ROS/casp-3/GSDME pathway, potentially offering a novel treatment option for reducing corneal opacity in FK.

摘要

目的

被（半胱天冬酶 - 3）激活后裂解的gasdermin E（GSDME），被认为是细胞焦亡中的关键执行者。然而，其在真菌性角膜炎（FK）中的作用仍不清楚。因此，我们分析了GSDME及其信号通路在烟曲霉（AF）诱导的FK中的作用。

方法

我们使用小鼠模型和人角膜上皮细胞进行实验。最初，我们在不同时间间隔用AF感染小鼠，并检查FK病变的进展情况，选择病变最严重的时间点。接下来，我们用各种可能影响细胞焦亡的细胞因子抑制剂对受试者进行预处理。然后，我们使用qRT-PCR、流式细胞术、透射电子显微镜以及蛋白质免疫印迹法评估FK病变的发展和炎性细胞因子的产生。

结果

确定小鼠和人角膜上皮细胞的最佳刺激时间分别为三天和十二小时。在小鼠和角膜上皮细胞模型中，GSDME均在活性氧（ROS）/半胱天冬酶 - 3/GSDME通路下游显著介导AF诱导的细胞焦亡，并极大地影响AF诱导的FK中的炎症过程和角膜炎。

结论

总体而言，GSDME在角膜炎症期间的细胞焦亡中起关键作用。通过调节细胞焦亡过程中白细胞介素 - 1β的释放，GSDME对FK中的宿主免疫反应有显著影响。阻断ROS/半胱天冬酶 - 3/GSDME通路可抑制这一过程，这可能为减轻FK中的角膜混浊提供一种新的治疗选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/e44d65dd9487/iovs-66-6-52-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/98091e30880a/iovs-66-6-52-f001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/ebd95f71286f/iovs-66-6-52-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/fceb983a241e/iovs-66-6-52-f004a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/366c17afb09b/iovs-66-6-52-f004b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/ab01bc180994/iovs-66-6-52-f005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/4b467fce104e/iovs-66-6-52-f005b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/9434bd9fdea8/iovs-66-6-52-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbe4/12178440/e44d65dd9487/iovs-66-6-52-f007.jpg

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