Nitrogen Species Modulate Macrophage ER Stress to Preserve Alveolar Bone: A Translational Adjunct for Periodontal Care

BACKGROUND: Periodontitis remains a leading cause of tooth loss, yet conventional therapeutic procedures show limited impact on host immune dysregulation and alveolar bone preservation. OBJECTIVES: To evaluate the feasibility and efficacy of a chairside-oriented, plasma-based nitrogen species implantation (PBNI) approach for nitric oxide (NO) delivery and to delineate the underlying host-modulatory mechanisms relevant to periodontal care. METHODS: In a ligature-induced mouse periodontitis model, we assessed inflammatory infiltration, leukocyte recruitment, macrophage polarization, and alveolar bone outcomes after PBNI. Transcriptomics of bone-marrow-derived macrophages (BMDMs) and targeted genetic perturbation probed the underlying pathways. Quantitative data were analyzed using appropriate statistical methods. RESULTS: PBNI reduced gingival inflammatory infiltration, decreased neutrophil/macrophage recruitment, promoted M2 repolarization, and increased alveolar bone volume. RNA sequencing revealed suppression of endoplasmic reticulum (ER) stress signatures with upregulation of Phlda1. Mechanistically, PBNI-derived NO correlates with elevated Phlda1 and downregulated ER-stress hub genes (Chac1, Ddit3/CHOP, Trib3, Herpud1, Sesn2, Hspa5/GRP78, Hyou1, Asns) in M1 macrophages. Genetic silencing of Phlda1 abrogated these benefits, establishing a required NO/Phlda1/ER-stress attenuation axis. CONCLUSIONS: By engaging the NO-Phlda1 axis and being associated with reduced macrophage ER stress, PBNI may serve as a practical adjunct strategy with potential to improve periodontal outcomes. CLINICAL RELEVANCE: These preclinical data support PBNI as a chairside host-modulatory adjunct to non-surgical periodontal therapy by restoring immune homeostasis and creating a bone-forming microenvironment. The approach is conceptually compatible with short, operator-delivered applications and standard infection-control workflows.