Circadian rhythm disruption aggravates periodontitis via orchestrating TREM2+ macrophage-mediated bone resorption

Circadian rhythm disruption (CRD) potently exacerbates periodontitis, yet how environmental circadian misalignment is sensed and transduced into localized inflammatory bone loss remains poorly understood. Using single-cell RNA sequencing of gingival tissues from a CRD-exacerbated mouse model, we identified a distinct macrophage subpopulation selectively expanded under CRD conditions and enriched along the osteoclastogenic trajectory. This subpopulation is characterized by high expression of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). The CRD-driven accumulation of TREM2⁺ macrophages positively correlated with the severity of alveolar bone destruction and increased osteoclast activity, alongside downregulation of the core circadian regulators BMAL1 within the periodontal microenvironment. TREM2 displays robust circadian oscillations in vitro, and CUT&Tag sequencing demonstrates that BMAL1 rhythmically binds the Trem2 promoter, establishing a clock-TREM2 regulatory axis. CRD disrupts this time-gated mechanism, leading to sustained TREM2 overexpression that pre-activates macrophages and drives excessive bone resorption. Local TREM2 inhibition alleviates gingival inflammation and reduces bone loss. Under RANKL stimulation, Bmal1 knockdown elevates TREM2 and the osteoclast master regulator NFATc1 across all circadian phases, indicating that inflammation-induced BMAL1 reduction relieves the circadian restriction on TREM2 expression. Collectively, these findings show that CRD disrupts BMAL1-mediated circadian gating of TREM2, and that restoring BMAL1 rhythmicity or directly inhibiting TREM2 may represent a therapeutic strategy to mitigate periodontitis exacerbated by circadian disruption.