2. Academic Validation
  3. Nitrogen Species Modulate Macrophage ER Stress to Preserve Alveolar Bone: A Translational Adjunct for Periodontal Care

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

  • Int Dent J. 2026 Apr;76(2):109400. doi: 10.1016/j.identj.2025.109400.
Zhixin Liu 1,  Laidi Wu 1,  Ming Luo 1,  Ollie Yiru Yu 2,  Xinpei Lu 3,  Yingguang Cao 1,  Ke Song 4
Affiliations

Affiliations

  • 1 School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, Hubei, China.
  • 2 Faculty of Dentistry, The University of Hongkong, Hong Kong SAR, China.
  • 3 College of Electrical and Electronic Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 4 School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, Hubei, China. Electronic address: [email protected].
PMID: 41637951 DOI: 10.1016/j.identj.2025.109400
Abstract

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.

Keywords

Dentistry; Endoplasmic reticulum stress; Nitric oxide; Orthodontics; Periodontitis; Phlda1.

Figures
Products