真菌性角膜炎
白色念珠菌
炎症体
生物
TLR4型
先天免疫系统
微生物学
S100A9型
免疫学
上睑下垂
半胱氨酸蛋白酶1
免疫系统
角膜炎
炎症
遗传学
作者
Xiaolong Fang,Huifang Lian,Shuang Liu,Jingcun Dong,Xin Hua,Wenguang Li,Chunyang Liao,Xiaoyong Yuan
出处
期刊:Research Square - Research Square
日期:2023-04-18
标识
DOI:10.21203/rs.3.rs-2807590/v1
摘要
Abstract Background Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. Methods Experimental fungal keratitis was established in wild-type and gene knockout mice by infecting mouse corneas with Candida albicans . The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, western blotting and immunohistochemistry were conducted in this research. Results Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. Conclusions The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.
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