Objective: Maternal sleep disorders are emerging risk factors for preeclampsia, yet the precise mechanisms bridging systemic sleep disorders to placental pathology and preeclampsia pathogenesis remain to be elucidated. Design and method: We combined a prospective clinical cohort of 413 pregnant women with a murine model of gestational sleep fragmentation designed to recapitulate clinical sleep architecture. We first characterized placental immune profiles using single-cell RNA sequencing and flow cytometry, followed by targeted metabolomics to identify upstream systemic drivers. Mechanistic studies integrated Seahorse bioenergetic analysis and CUT&Tag sequencing. The functional hierarchy was rigorously established using neutrophil depletion, adoptive transfer, conditional knockout mice, and pharmacological interventions targeting neutrophil extracellular traps (NETs) and Toll-like receptor 2 (TLR2). 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 at the Tlr2 promoter. This epigenetic modification upregulated Toll-like receptor 2 (TLR2), which functioned as a priming mechanism to increase neutrophil susceptibility to NET formation within the placental microenvironment. Finally, therapeutic targeting of this signaling cascade via specific TLR2 inhibition effectively ameliorated sleep disorder-induced preeclampsia. Conclusions: Our study identifies a hierarchical immunometabolic axis linking maternal sleep disorders to preeclampsia. We demonstrate that sleep disorders prime placental pathology via glucocorticoid receptor-dependent neutrophil metabolic reprogramming and H3K18 lactylation. These findings identify TLR2 as a specific therapeutic target for sleep-associated pregnancy complications.
Zhu et al. (2026) studied this question.