Neuro-Immune Crosstalk via Substance P Regulates Periodontal Bone Loss

Objectives: Periodontitis is a highly prevalent infectious disease which progressively destroys the bone surrounding teeth, leading to tooth loss. Periodontal tissue is innervated by abundant primary afferents expressing neuropeptides, such as substance P, and transient receptor potential vanilloid 1 (TRPV1). Previously, we showed that TRPV1 expressing afferents modulate bone destruction in mouse periodontitis model. Chemical ablation or chemogenetic silencing of TRPV1 expressing afferents decreased host responses in periodontia and ligature-induced bone loss in mice. However, the role of substance P in regulating host immune responses in periodontal inflammation is not well known. In this study, we aimed to test the hypothesis that substance P increase bone destruction in periodontitis via regulation of host immune response.
Methods: A ligature-induced periodontitis was initiated in mice by placing a 5–0 silk ligature around the maxillary left second molar for 2 weeks. SP or vehicle (1mg/site) was locally injected twice a day around M2 for five days. Results were evaluated using micro-CT, Immunohistochemistry, Histology, Luminex assay & Flow cytometry.
Results: Knock out of SP (Tac1^−/−) showed significant reduction in ligature induced bone loss compared to WT. Further, SP injection greatly enhanced ligature-induced bone loss compared to vehicle. Histological examination showed decreased bone loss after ligature in Tac1 KO mice compared to WT, which was accompanied by reduced numbers of osteoclasts. Furthermore, proportion of immune cells (CD45+ leukocytes and neutrophils) from gingiva were significantly limited in Tac1 KO than WT. Cytokines associated with alveolar bone loss such as TNF, IL1b, and RANKL, were significantly lower in periodontium of Tac1 KO than WT at 2 weeks after ligature.
Conclusions: We conclude that the responses of host to periodontal infection is modulated by TRPV1+ afferents, acting through SP, which is a novel neuroimmune axis that can be targeted for treating periodontitis.