2. Academic Validation
  3. Targeting periodontal inflammatory microenvironment to ameliorate periodontitis: A nitrogen ions implantation technique

Targeting periodontal inflammatory microenvironment to ameliorate periodontitis: A nitrogen ions implantation technique

  • Int Immunopharmacol. 2026 Feb 1:170:116055. doi: 10.1016/j.intimp.2025.116055.
Zhixin Liu 1,  Laidi Wu 1,  Xinpei Lu 2,  Ke Song 3,  Yingguang Cao 4
Affiliations

Affiliations

  • 1 Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hanghang Road, Hankou, Wuhan 430030, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China.
  • 2 State Key Laboratory of Advanced Electromagnetic Engineering and Technology, School of Electrical and Electronic Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 3 Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hanghang Road, Hankou, Wuhan 430030, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China. Electronic address: songke_coco@163.com.
  • 4 Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hanghang Road, Hankou, Wuhan 430030, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China. Electronic address: cyg0729@tjh.tjmu.edu.cn.
PMID: 41448003 DOI: 10.1016/j.intimp.2025.116055
Abstract

Periodontitis, an inflammatory disease affecting over 45 % of adults globally, causes irreversible alveolar bone loss through immune cells-mediated inflammation, thus necessitating novel regenerative therapies. This study proposes a cold plasma-based nitrogen species implantation (PBNI) technique to regulate the periodontal immune microenvironment and ameliorate periodontal inflammation. This study demonstrates that PBNI, optimizing for nitric oxide (NO) delivery, reprograms macrophage phenotype to resolve inflammation and reduce alveolar bone resorption. The linear correlation between exposure time and NO yield establishes PBNI as a tunable NO delivery approach. In mice with experimental periodontitis, PBNI increased alveolar bone volume, the effects of which were mirrored by the NO donor L-arginine. High-throughput RNA Sequencing of bone marrow-derived macrophages (BMDMs) exposed to PBNI identified a cluster of differentially expressed genes responding to the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/AMP-activated protein kinase (AMPK) pathways significantly enriched. Mechanistically, PBNI-derived NO activates the canonical soluble Guanylate Cyclase/Protein Kinase G (sGC/PKG) cascade and a newly identified phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1)/Akt1/AMPKα1 axis, synergistically driving the M2 macrophage repolarization. Crucially, NO scavenging or PI3K pathway inhibition abrogated M2 repolarization and alveolar bone regeneration. This study establishes a tunable NO delivery approach that coordinates sGC/PKG and PIK3AP1/Akt1/AMPKα1 signaling to reprogram periodontal inflammatory microenvironment. By resolving the mechanism of PBNI and enhancing its osteogenic efficacy through controlling NO release, we provide a clinically translatable strategy for immunomodulatory periodontal regeneration therapy.

Keywords

AMPKα1; Macrophage repolarization; Nitric oxide; PI3K/AKT pathway; Periodontal inflammation; Plasma-based nitrogen species implantation.

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