坏死性下垂
炎症体
促炎细胞因子
真菌性角膜炎
角膜炎
裂谷1
细胞生物学
生物
免疫学
炎症
程序性细胞死亡
细胞凋亡
生物化学
遗传学
作者
Bowen Wang,Xue Yang,Xi‐Nian Zuo,Hanmin Zeng,Xiaoran Wang,Huaxing Huang,Dalian He,Li Wang,Hong Ouyang,Jingjie Yuan
标识
DOI:10.1016/j.ajpath.2023.04.004
摘要
Fungal keratitis remains a major cause of severe visual loss in developing countries because of limited choices of therapy. The progression of fungal keratitis is a race between the innate immune system and the outgrowth of fungal conidia. Programmed necrosis (necroptosis), a type of proinflammatory cell death, has been recognized as a critical pathologic change in several diseases. However, the role and potential regulatory mechanisms of necroptosis have not been investigated in corneal diseases. The current study showed, for the first time, that fungal infection triggered significant corneal epithelial necroptosis in human/mouse/in vitro models. Moreover, a reduction in excessive reactive oxygen species release effectively prevented necroptosis. NLRP3 knockout did not affect necroptosis in vivo. In contrast, ablation of necroptosis via RIPK3 knockout significantly delayed migration and inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in macrophages, which enhanced the progression of fungal keratitis. Taking these findings together, the study indicated that overproduction of reactive oxygen species in fungal keratitis leads to significant necroptosis in the corneal epithelium. Furthermore, the necroptotic stimuli-mediated NLRP3 inflammasome serves as a driving force in host defense against fungal infection.
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