Local Neuro-immunomodulatory Mechanism in Periodontitis: A Systematic Review.

Background: Emerging evidence indicates that bidirectional neuroimmune communication within the local periodontal microenvironment modulates the progression of periodontitis. However, the underlying neuro-immunomodulatory mechanisms remain incompletely understood. Objective: This systematic review evaluates and synthesizes current evidence on local neuro-immune signalling pathways and neuromodulator molecules altering periodontitis pathogenicity. Methods: Following PROSPERO registration (CRD42025111365), a comprehensive literature search was conducted per PRISMA 2000 guidelines across PubMed, Cochrane Library, Google Scholar, Web of Science, ScienceDirect, and Scopus databases (January 2012–January 2026, English-language). Quality assessment was independently performed by two calibrated authors and a third reviewer using the Quin, SYRCLE, and NOS risk of bias tools. Results: 3 eligible studies out of 1401 research papers that focused on periodontitis were selected based on eligibility criteria. Gingival solitary chemosensory cells (gSCC) detected bacterial quorum-sensing molecules through Tas2r–α-gustducin signalling, triggering innate immunity that leads to increased production of antimicrobial peptides. Disruption of gSCC increased bacterial burden and accelerated alveolar bone loss. M2 macrophages secrete cytokines IL-10 and TGF-β, which exhibit anti-inflammatory and tissue repair functions. Cholinergic signalling may contribute to the progression of periodontitis. In periodontitis, the release of acetylcholine from neurons into the gingival crevicular fluid enhances the secretion of chemokines CXCL1 and CXCL8, promoting the repair of the epithelial barrier. Conclusion: Although current evidence is largely preclinical, further mechanistic and clinical studies are warranted to elucidate local neuro-immunomodulatory circuits in periodontal homeostasis.