Serine Promotes Inflammatory Macrophage Polarisation in Periodontitis via NAD⁺ Signalling

To investigate the role of serine in modulating macrophage polarisation and periodontal inflammation.

Saliva samples were obtained from periodontitis patients, healthy individuals and periodontitis remission patients for salivary metabolomics analysis. C57BL/6J mice were used to establish a ligature-induced periodontitis model. THP-1 cells were used in vitro to explore the mechanism underlying serine-mediated periodontitis. Micro-computed tomography, immunohistochemistry, quantitative real-time polymerase chain reaction, flow cytometry, western blotting, RNA sequencing and NAD⁺/NADH detection were performed to explore the role of serine in periodontitis and the underlying mechanism.

Salivary serine concentrations were significantly elevated in patients with periodontitis and correlated with disease severity. In vivo experiments showed that locally elevated serine concentrations exacerbated alveolar bone resorption in a mouse model of periodontitis. Transcriptomic analysis revealed that serine stimulation activated inflammation-related pathways, particularly the nicotinamide salvage pathway, which modulates NAD⁺ levels. Inhibition of intracellular serine transport using L-phenylglycine (L-phg) and mitochondrial complex I (MCI) activity using rotenone reduced inflammatory macrophage polarisation, decreased inflammatory markers and alleviated periodontal tissue damage.

Serine-induced inflammatory macrophage polarisation, mediated through NAD⁺ signalling, plays a key role in periodontitis pathogenesis. Targeting serine transport and NAD⁺ metabolism may offer new therapeutic strategies for managing periodontitis.