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.

Keywords: Bromodomain; DNA methylation; Epigenetics; Histone deacetylase; Inflammation; Periodontitis; Porphyromonas gingivalis.

Fig. 1

Schematic representation of the biochemical processes involved in DNA methylation and histone acetylation. a Unmethylated cytosine at the CpG site can be methylated de novo by DNMT3A or DNMT3B in complex with DNMT3L, the latter lacking methyltransferase activity. The DNMT1:UHRF1 complex is responsible for the conservation of the CpG methylation pattern on the complementary DNA strand after replication. TET enzymes catalyze the formation of oxidized 5mC derivatives, which are no longer recognized by the DNMT1:UHRF1 complex (passive demethylation). Additionally, 5fC and 5caC can be recognized and excised by TDG, leading to replacement with unmodified cytosine through BER (active demethylation). b N-terminal lysine residues on histone tails are acetylated by HATs, which leads to neutralization of their positive charge, relaxation of chromatin structure, and increased transcriptional accessibility of gene promoters. Bromodomain-containing proteins recognize specific acetyl-lysine containing sequences within the histone, promoting the formation of acetylation-dependent transcriptional complexes. Acetylated lysine residues can be deacetylated by HDACs. BER base-excision repair, DNMT DNA methyltransferase, HAT histone acetyltransferase, HDAC histone deacetylase, TET ten-eleven translocation, TDG thymine DNA glycosylase, UHRF1 Ubiquitin-like, containing PHD and RING finger domains-1

Fig. 2

Model of epigenetic regulation of TLR2 expression in GECs. Cell responses to P. gingivalis are predominantly mediated by engagement of TLR2. Under physiological conditions, P. gingivalis-induced activation of TLR2 stimulates the production of inflammatory cytokines, chemokines and antimicrobial peptides that promote pathogen elimination by the immune system. Chronic exposure to P. gingivalis, through an unknown mechanism, induces increased TLR2 promoter methylation in GECs, which was also observed in cells from a subgroup of periodontitis patients [111]. TLR2 promoter hypermethylation is associated with reduced TLR2 expression and diminished production of inflammatory mediators and antimicrobial peptides normally induced by the pathogen [111]. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License