The endothelial PECAM1–CXCR4 axis amplifies neutrophil degranulation to exacerbate sleep-deprived periodontitis: a systems-level framework for comorbidity therapy

Abstract

Sleep deprivation (SD) is a known risk factor for periodontitis (PD), but the molecular bridge connecting this systemic stressor to local inflammation remains elusive. Here, through a systems-level investigation integrating human epidemiology, multi-omics, and disease modeling, we uncover a novel endothelial-neutrophil axis that drives SD-aggravated periodontitis.. We first confirmed in human cohorts and mouse models that SD exacerbates neutrophil-mediated periodontal bone loss. Integrative bioinformatic analysis pinpointed endothelial PECAM1 and neutrophil CXCR4 as core co-regulated hubs.Mechanistically, we reveal a paradoxical process: under inflammatory conditions, endothelial PECAM1 acts as a high-affinity “decoy receptor” for the chemokine CXCL12, sequestering it within the vascular niche. This ligand scarcity triggers a compensatory upregulation of its receptor, CXCR4, on neutrophils. Consequently, these “primed” neutrophils become hyper-reactive, leading to excessive degranulation and tissue destruction upon stimulation. Leveraging this mechanism, we computationally identified and experimentally validated curcumin as a dual inhibitor of PECAM1 and CXCR4. In our comorbidity mouse model, curcumin not only blocked this pathological axis to mitigate periodontal destruction but also partially restored NREM sleep architecture. Our findings establish the PECAM1-CXCR4 decoy axis as a critical, druggable pathway in sleep-inflammation comorbidity and provide a conceptual framework for treating complex systemic-local disorders.