Macrophage functional plasticity in periodontitis: microenvironmental regulation, disease progression, and therapeutic targeting
- 1Department of Periodontology, The First Affiliated Hospital of Xinjiang Medical University (Affiliated Stomatological Hospital), Urumqi, Xinjiang, China
- 2Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 3School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
Abstract
Periodontitis is a chronic inflammatory disease driven by periodontal microbial dysbiosis and dysregulated host immune responses. Its progression is characterized by persistent inflammation, destruction of periodontal soft tissues, disrupted alveolar bone remodeling, and impaired tissue repair. As key effector cells within the periodontal immune microenvironment, macrophages contribute to pathogen clearance, inflammatory regulation, bone homeostasis, and tissue repair. Macrophage responses are highly heterogeneous and context dependent, extending well beyond the conventional M1/M2 dichotomy. This review focuses on macrophage functional plasticity in periodontitis, defined here as context-dependent changes in macrophage functional responses rather than heterogeneity or state-associated signatures alone, and examines how periodontal microorganisms and their virulence factors, host inflammatory signals, hypoxia and oxidative stress, immunometabolic changes, and epigenetic and post-transcriptional mechanisms regulate these responses. We further discuss how these responses contribute to inflammatory amplification, extracellular matrix degradation, alveolar bone resorption, resolution of inflammation, and periodontal tissue repair. Emerging evidence indicates that macrophage dysregulation in periodontitis extends beyond an imbalance between pro-inflammatory and repair-associated functions to include alterations in macrophage subset composition and selected functional programs. Direct evidence tracking transitions within macrophage populations in periodontal lesions, however, remains limited. The strategies reviewed here target inflammatory pathways, immunometabolism, intercellular communication, and the local tissue microenvironment. Linking changes in macrophage function to tissue outcomes may clarify the immunopathogenesis of periodontitis and inform treatments that promote inflammation resolution and periodontal regeneration.
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BibTeX
@article{gu2026macrophage,
title = {{Macrophage functional plasticity in periodontitis: microenvironmental regulation, disease progression, and therapeutic targeting}},
author = {Ziqi Gu and Xinyu Li and Gulinur Awuti},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1973755},
url = {https://doi.org/10.3389/fimmu.2026.1973755},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Macrophage functional plasticity in periodontitis: microenvironmental regulation, disease progression, and therapeutic targeting
AU - Ziqi Gu
AU - Xinyu Li
AU - Gulinur Awuti
PY - 2026
DA - 2026/10/12
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1973755
UR - https://doi.org/10.3389/fimmu.2026.1973755
AB - Periodontitis is a chronic inflammatory disease driven by periodontal microbial dysbiosis and dysregulated host immune responses. Its progression is characterized by persistent inflammation, destruction of periodontal soft tissues, disrupted alveolar bone remodeling, and impaired tissue repair. As key effector cells within the periodontal immune microenvironment, macrophages contribute to pathogen clearance, inflammatory regulation, bone homeostasis, and tissue repair. Macrophage responses are highly heterogeneous and context dependent, extending well beyond the conventional M1/M2 dichotomy. This review focuses on macrophage functional plasticity in periodontitis, defined here as context-dependent changes in macrophage functional responses rather than heterogeneity or state-associated signatures alone, and examines how periodontal microorganisms and their virulence factors, host inflammatory signals, hypoxia and oxidative stress, immunometabolic changes, and epigenetic and post-transcriptional mechanisms regulate these responses. We further discuss how these responses contribute to inflammatory amplification, extracellular matrix degradation, alveolar bone resorption, resolution of inflammation, and periodontal tissue repair. Emerging evidence indicates that macrophage dysregulation in periodontitis extends beyond an imbalance between pro-inflammatory and repair-associated functions to include alterations in macrophage subset composition and selected functional programs. Direct evidence tracking transitions within macrophage populations in periodontal lesions, however, remains limited. The strategies reviewed here target inflammatory pathways, immunometabolism, intercellular communication, and the local tissue microenvironment. Linking changes in macrophage function to tissue outcomes may clarify the immunopathogenesis of periodontitis and inform treatments that promote inflammation resolution and periodontal regeneration.
SN - 1664-3224
ER -