Deciphering S1P downregulation and sphingolipid homeostasis disruption in fungal keratitis via multi-omics and MALDI-MSI analysis

作者：Zhenyuan Fu, Jing Zhong, Lixia Lin, Jiahui Yang, Yichen Xiao, Lei Li, Jing Zhang, Jin Yuan · 发表于：The Ocular Surface · 年份：2024 · DOI：10.1016/j.jtos.2024.12.001 · 被引用次数：5 · 研究领域：Sphingolipid Metabolism and Signaling、Spondyloarthritis Studies and Treatments、Fungal Infections and Studies

PURPOSE: The absence of effective treatment strategies in Fungal Keratitis (FK) emphasizes the critical need to understand the pathogenic mechanisms to enhance therapeutic outcomes. Sphingolipids have been proved to play a pivotal role in the pathogenesis of fungal infections, but the specific alteration in sphingolipids and regulatory pathways remain elusive. Our aim is to gain insight into the pathophysiological mechanisms of sphingolipid homeostasis in FK through multi-omics analysis. METHODS: Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was performed in FK patients and mouse model. Furthermore, time-course RNA-seq was performed and Weighted gene co-expression network analysis (WGCNA) was used to reveal the driver genes in FK. We further investigated the effect of FTY-720, a mimetic of sphingosine 1-phosphate (S1P), on the progression of FK. RESULTS: MALDI-MSI analysis of FK patients revealed a downregulation of sphingolipids, with sphingolipid metabolism identified as the most prominently enriched pathway. These alterations were validated in mouse model, in which S1P, ceramide, ceramide 1-phosphate and sphingomyelin were found to be downregulated. Time-course transcriptomic analysis suggests that degradation of sphingolipids by specific enzymes drives the progression of FK, involving phospholipid degradation, downregulation of TOR pathway, and activation of innate immune response. Consequently, epithelial cell function was inhibited an...