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Microplastics modulate neutrophil migration via an ROS histone lactylation positive feedback loop
Summary
Using zebrafish, researchers showed that microplastic exposure at 100 µg/L increased neutrophil migration to inflammation sites by up to 1.7-fold, and identified a reactive oxygen species–histone lactylation positive feedback loop as the underlying regulatory mechanism. The findings reveal a novel epigenetic pathway through which microplastics dysregulate immune responses.
Microplastics (MPs) have attracted considerable attention due to their significant toxic effects. Although previous studies have reported their impact on neutrophil function, the real-time visualization and regulatory mechanisms of MP-induced neutrophil migration in live organisms remain unexplored. In this study, zebrafish were exposed to 100 μg/L MPs, resulting in a 1.7-fold and 1.5-fold increase in neutrophil migration to inflammatory sites at 3 h and 6 h, respectively. Transcriptomic analysis suggested the involvement of reactive oxygen species (ROS) and histone lactylation in this process. Experimental validation confirmed that MPs significantly upregulated lactylation levels, with related genes (e.g., ep300a, ep300b, ldha) and proteins (Pan-Kla, H3K18la) increased by approximately 50 %. Concurrently, pro-inflammatory cytokines (il-6, il-8, il-1β) were elevated by nearly 1-fold, ROS levels were raised by 1.4-fold, and oxidative stress-related genes (sod2, gpx2) were significantly upregulated. Inhibition of lactate production with 2DG or suppression of oxidative stress with Dpi restored neutrophil migration to near baseline levels. Mechanistically, lactylation-specific ChIP-seq and ChIP-qPCR analyses revealed that H3K18la modification promotes duox expression, thereby enhancing ROS generation. ROS, in turn, further amplifies lactylation, establishing a positive feedback loop that collectively drives neutrophil migration. This study provides the first real-time visualization of MP-induced neutrophil migration in vivo and elucidates the underlying ROS-lactylation interaction mechanism, offering new insights and experimental evidence for understanding the immunotoxicity of MPs.