Maternal sleep disorders drive preeclampsia via immunometabolic reprogramming of neutrophils

Background Sleep disorders are highly prevalent among pregnant women and are critical emerging risk factors for preeclampsia; however, the precise mechanisms bridging sleep disorders to preeclampsia pathogenesis remain to be elucidated. Methods A prospective clinical cohort of pregnant women was integrated with a murine model of gestational sleep fragmentation. Placental immune profiles were characterized via single-cell RNA sequencing, followed by targeted metabolomics to identify upstream drivers. Metabolic and epigenetic signatures were evaluated to determine the underlying mechanisms. Genetically modified mice and pharmacological interventions were used to validate pathogenic phenotypes and molecular targets. Results In our clinical cohort, poor sleep quality was significantly associated with the incidence of hypertensive disorders of pregnancy. In mice, sleep fragmentation recapitulated core preeclampsia-like phenotypes, driven by placental neutrophil infiltration and excessive neutrophil extracellular trap (NET) formation. Neutrophil depletion or inhibition of neutrophil extracellular traps significantly rescued these disease phenotypes. Mechanistically, sleep disorders-induced systemic corticosterone elevation activated the glucocorticoid receptor in neutrophils to orchestrate a metabolic switch toward aerobic glycolysis. The resulting intracellular lactate accumulation fueled histone H3 lysine 18 lactylation (H3K18la) at the TLR2 promoter. This epigenetic modification upregulated Toll-like receptor 2 (TLR2) expression, which functioned as a priming mechanism to increase neutrophil susceptibility to NET formation within the placental microenvironment. Finally, TLR2 inhibition effectively ameliorated sleep disorder-induced preeclampsia in mice. Conclusions Our study identifies a hierarchical immunometabolic axis linking maternal sleep disorders to preeclampsia. We demonstrate that sleep disorders induce placental injury via glucocorticoid receptor-dependent metabolic reprogramming and H3K18la modification in neutrophils. These findings identify TLR2 as a promising therapeutic target for sleep disorder-associated pregnancy complications.