Liu_2025_Adv.Sci.(Weinh)__e00945

Continuous sleep deprivation (SD) triggers systemic inflammatory storm and immune dysregulation, yet its specific impact on periodontitis and the corresponding therapeutic interventions remains unclear. Consequently, this study elucidates the neuroimmune mechanisms linking SD to ligature-induced periodontitis (LIP) in mice and evaluates electroacupuncture (EA) as a novel adjunctive therapy. Screening analyses (ELISA, public databases, flow cytometry, immunofluorescence, etc.) identified pivotal roles of acetylcholine (ACh), alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and acetylcholinesterase (AChE) in SD-aggravated periodontitis with a decrease in ACh levels, down-regulation of alpha7nAChR on macrophages, and an increase in trigeminal ganglion-derived AChE. Clinical validation in periodontitis patients with poor sleep (PSQI <= 5) confirmed this tripartite cholinergic imbalance. Ultimately, both in vivo and in vitro data demonstrated that EA inhibits M1 polarization while promoting M2 polarization of macrophages through alpha7nAChR activation. Therefore, SD exacerbates periodontitis via the AChE-ACh-alpha7nAChR axis-mediated trigeminal-periodontal neuroimmune pathway, whereas EA partially reverses this pathology by targeting macrophage alpha7nAChR. These findings reveal new insights into the "oral-brain axis" in oral disease pathogenesis and provide novel therapeutic strategies for periodontitis patients with comorbid sleep disorders.