Rev-Erbα Connects Circadian Rhythm To Periodontitis Via Neutrophil Recruitment

Aim to conduct a thorough investigation of the immunopathological mechanism of periodontitis. Explore whether the activity of neutrophils in periodontal tissue is regulated by circadian rhythm. The study was approved by the Medical Ethics Committee of TJMU, HUST ([2023] S207) and the IACUC, HUST (Number:4279). Periodontal samples were collected from periodontally healthy individuals at three distinct time periods: morning, afternoon, evening . Male C57BL/6J mice (6-7 weeks old) were kept in a standard 12:12 light-dark cycle or jet lag schedule in SPF environments with standard food and water. Human neutrophils were isolated from the peripheral blood of healthy volunteers using a neutrophil isolation kit. Human gingival fibroblasts (HGFs) were obtained from periodontal healthy volunteers undergoing third molar extraction. Clinical samples revealed time-of-day-dependent neutrophil counts and cytokine levels in healthy gingiva. Murine studies demonstrated diurnal oscillations in neutrophil recruitment and CXCL1/CXCL2/CXCL5 expression, peaking during late active phase, coinciding with heightened immune responses to pathogenic stimuli. Mechanistically, in periodontitis, gingival fibroblast REV-ERBα transcriptionally regulates chemokine-driven neutrophil rhythms, while NF-κB-mediated inflammatory signals disrupt this oscillation, causing sustained neutrophil infiltration. Notably, topical REV-ERBα agonist administration during late active phase attenuated periodontitis-induced bone loss. A direct link exists between circadian rhythms and periodontal innate immunity. In periodontitis, inflammatory signals suppress REV-ERBα via the NF-κB pathway, triggering excessive neutrophil infiltration in periodontal tissues. Targeting REV-ERBα represents a promising therapeutic strategy for periodontitis.