Histone lactylation-ROS loop contributes to light exposure-exacerbated neutrophil recruitment in zebrafish

LIGHT serves as a crucial external zeitgeber for maintaining and restoring physiological homeostasis in most organisms. Disrupting of LIGHT rhythms often leads to abnormal immune function, characterized by excessive inflammatory responses. However, the underlying regulatory mechanisms behind this phenomenon remain unclear. To address this concern, we use in vivo imaging to establish inflammation models in zebrafish, allowing us to investigate the effects and underlying mechanisms of LIGHT disruption on neutrophil recruitment. Our findings reveal that under sustained LIGHT conditions (LL), neutrophil recruitment in response to caudal fin injury and otic vesicle inflammation is significantly increased. This is accompanied by elevated levels of histone (H3K18) lactylation and Reactive Oxygen Species (ROS) content. Through ChIP-sequencing and ChIP‒qPCR analysis, we discover that H3K18 lactylation regulates the transcriptional activation of the duox gene, leading to ROS production. In turn, ROS further promote H3K18 lactylation, forming a positive feedback loop. This loop, driven by H3K18 lactylation-ROS, ultimately results in the over recruitment of neutrophils to inflammatory sites in LL conditions. Collectively, our study provides evidence of a mutual loop between histone lactylation and ROS, exacerbating neutrophil recruitment in LIGHT disorder conditions, emphasizing the significance of maintaining a proper light-dark cycle to optimize immune function.