Epigenetic regulation of inflammation in periodontitis: cellular mechanisms and therapeutic potential

Abstract

Epigenetic mechanisms, namely DNA and histone modifications, are critical regulators of immunity and inflammation which have emerged as potential targets for immunomodulating therapies. The prevalence and significant morbidity of periodontitis, in combination with accumulating evidence that genetic, environmental and lifestyle factors cannot fully explain the susceptibility of individuals to disease development, have driven interest in epigenetic regulation as an important factor in periodontitis pathogenesis. Aberrant promoter methylation profiles of genes involved in inflammatory activation, including TLR2, PTGS2, IFNG, IL6, IL8, and TNF, have been observed in the gingival tissue, peripheral blood or buccal mucosa from patients with periodontitis, correlating with changes in expression and disease severity. The expression of enzymes that regulate histone acetylation, in particular histone deacetylases (HDACs), is also dysregulated in periodontitis-affected gingival tissue. Infection of gingival epithelial cells, gingival fibroblasts and periodontal ligament cells with the oral pathogens Porphyromonas gingivalis or Treponema denticola induces alterations in expression and activity of chromatin-modifying enzymes, as well as site-specific and global changes in DNA methylation profiles and in histone acetylation and methylation marks. These epigenetic changes are associated with excessive production of inflammatory cytokines, chemokines, and matrix-degrading enzymes that can be suppressed by small molecule inhibitors of HDACs (HDACi) or DNA methyltransferases. HDACi and inhibitors of bromodomain-containing BET proteins ameliorate inflammation, osteoclastogenesis, and alveolar bone resorption in animal models of periodontitis, suggesting their clinical potential as host modulation therapeutic agents. However, broader application of epigenomic methods will be required to create a comprehensive map of epigenetic changes in periodontitis. The integration of functional studies with global analyses of the epigenetic landscape will provide critical information on the therapeutic and diagnostic potential of epigenetics in periodontal disease.

Periodontal Inflammation and Systemic Diseases: An Overview

“…Epigenetic regulation of inflammation has been studied in the context of periodontitis by Jurdziński et al ( 2020 ). These authors argue that a deeper understanding of these epigenetic regulatory mechanisms will provide clues about functions at the cellular level with potential therapeutic impact.…”

The Emerging Regulatory Role of Circular RNAs in Periodontal Tissues and Cells

“…Epigenetic-associated ncRNAs can be divided into two main groups—small ncRNAs (<30 nts) and long ncRNA (>200 nts). The potential role of epigenetics-related ncRNAs in diagnosing periodontitis was investigated previously in PDL and gingiva tissues [ 21 , 22 , 23 , 24 ]; however, most reviews of this topic focused mainly on the role of small non-coding RNAs (i.e., microRNA). The information gap in periodontology in terms of the significance of long non-coding RNA molecules (i.e., circular RNAs), both in the context of periodontal pathogenesis and regeneration, is addressed in this review.…”

Resolving the Contradictory Functions of Lysine Decarboxylase and Butyrate in Periodontal and Intestinal Diseases

“…Sirtuin production and serum levels should therefore decrease in periodontitis but increase after therapy, as recently reported [ 181 ]. More importantly, a change or deterioration in any chronic inflammatory condition will dysregulate sirtuin 1 homeostasis [ 182 ]. For example, a failure to treat periodontitis decreases serum sirtuin levels and increases the severity of type 2 diabetes [ 175 ], whereas a failure to treat diabetes likewise increases systemic inflammation, decreases serum sirtuin levels, and promotes a greater likelihood of periodontal tooth loss [ 12 ].…”