Adipose Tissue Macrophages as Initiators of Exacerbated Periodontitis in Estrogen‐Deficient Environments via the Amplifier Extracellular Vesicles

Abstract Periodontitis in menopausal women tends to exacerbate, potentially resulting in tooth loss and increased risk of systemic diseases. The prior research demonstrates that pro‐inflammatory changes in macrophages under estrogen deficiency exacerbate periodontitis. However, the primary environmental factors contributing to the alteration of monocyte‐macrophages remain unknown. Recent studies, including animal models and clinical trials, have found a correlation between accumulation of visceral adipose tissue (VAT) and periodontitis progression in postmenopausal women. In estrogen‐deficient mice, macrophages in VAT show a pro‐inflammatory state. Removing VAT alleviates periodontitis in OVX mice. DNA methylation sequencing shows increased methylation in macrophages, especially Jazf1 hypermethylation, inhibiting its expression and promoting inflammation. Subsequently, small extracellular vesicles (sEVs) derived from pro‐inflammatory macrophages further intensify M1‐like polarization in resting macrophages, carrying inflammatory microRNAs like miR‐30e‐5p. Overall, this study proposes a novel perspective: periodontal pathogens act as initial triggers for inflammation, while chronic systemic inflammation, worsened by estrogen deficiency, is the main factor that exacerbates periodontitis. Pro‐inflammatory macrophages in VAT release sEVs, which activate resting macrophages into a pro‐inflammatory state upon encountering periodontal pathogens, resulting in persistent inflammation. Addressing the root causes of this dysregulation can lead to new therapeutic strategies for periodontitis and systemic inflammatory conditions, particularly in postmenopausal women.