Eldecalcitol alleviates diabetic periodontitis by regulating macrophage efferocytosis and polarization via SOCE machinery.

Diabetes exacerbates the occurrence and severity of periodontitis, the pathogenesis of diabetic periodontitis (DPD) is influenced by the delayed resolution of inflammation. Eldecalcitol (ED-71) has shown promise in preventing bone loss in DPD. We herein aimed to investigate the role of ED-71 in the inflammatory regression phase of DPD and elucidate the underlying mechanisms. Type-2 diabetes was induced by streptozotocin injection in Wistar rats, and to explore the in vivo effect of ED-71 on macrophage efferocytosis, periodontitis was induced by ligation combined with lipopolysaccharide. Alveolar bone destruction was assessed using micro-computed tomography, hematoxylin-eosin, immunohistochemistry, and tartrate-resistant acid phosphatase staining. Immunofluorescence staining and flow cytometry detected neutrophils, apoptotic cells, and macrophage polarization in periodontal tissue. Additionally, flow cytometry, real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to examine macrophage efferocytosis and changes in store-operated calcium entry (SOCE). We found that rats with diabetes exhibited more severe alveolar bone destruction and increased neutrophil aggregates in periodontal tissue. Following the ED-71 administration, alveolar bone loss significantly decreased, and the immune microenvironment of periodontal tissue tended to suppress inflammation. Macrophages stimulated with high glucose experienced disruption of SOCE machinery, leading to the inhibition of efferocytosis in vitro. ED-71 demonstrated the ability to restore macrophage efferocytosis by correcting SOCE, and preventing sustained inflammatory damage to periodontal tissue. In conclusion, diabetes impairs macrophage efferocytosis and M2 polarization in periodontitis rats, resulting in the delayed resolution of inflammation. ED-71 could attenuate alveolar bone loss by mitigating macrophage via SOCE machinery in DPD.