MicroRNAs: Harbingers and shapers of periodontal inflammation

Abstract

Periodontal disease is an inflammatory reaction of the periodontal tissues to oral pathogens. In the present review we discuss the intricate effects of a regulatory network of gene expression modulators, microRNAs (miRNAs), as they affect periodontal morphology, function and gene expression during periodontal disease. These miRNAs are small RNAs involved in RNA silencing and post-transcriptional regulation and affect all stages of periodontal disease, from the earliest signs of gingivitis to the regulation of periodontal homeostasis and immunity and to the involvement in periodontal tissue destruction. MiRNAs coordinate periodontal disease progression not only directly but also through long non-coding RNAs (lncRNAs), which have been demonstrated to act as endogenous sponges or decoys that regulate the expression and function of miRNAs, and which in turn suppress the targeting of mRNAs involved in the inflammatory response, cell proliferation, migration and differentiation. While the integrity of miRNA function is essential for periodontal health and immunity, miRNA sequence variations (genetic polymorphisms) contribute toward an enhanced risk for periodontal disease progression and severity. Several polymorphisms in miRNA genes have been linked to an increased risk of periodontitis, and among those, miR-146a, miR-196, and miR-499 polymorphisms have been identified as risk factors for periodontal disease. The role of miRNAs in periodontal disease progression is not limited to the host tissues but also extends to the viruses that reside in periodontal lesions, such as herpesviruses (human herpesvirus, HHV). In advanced periodontal lesions, HHV infections result in the release of cytokines from periodontal tissues and impair antibacterial immune mechanisms that promote bacterial overgrowth. In turn, controlling the exacerbation of periodontal disease by minimizing the effect of periodontal HHV in periodontal lesions may provide novel avenues for therapeutic intervention. In summary, this review highlights multiple levels of miRNA-mediated control of periodontal disease progression, (i) through their role in periodontal inflammation and the dysregulation of homeostasis, (ii) as a regulatory target of lncRNAs, (iii) by contributing toward periodontal disease susceptibility through miRNA polymorphism, and (iv) as periodontal microflora modulators via viral miRNAs.

Keywords: Inflammation; Long non-coding RNAs; MicroRNAs; Periodontal disease; Polymorphism; Viral microRNAs.

Figure 1.. MicroRNAs shape all aspects of periodontal inflammation.

This sketch illustrates the multiple sites of action and diverse functions of miRs in the regulation of periodontal inflammation, some of which are reviewed in this article, including (i) miRs involved in the gingival response against pathogens, (ii) miRs involved in periodontal homeostasis, (iii) viral miRs. In turn miR function is altered by sponge-like long non-coding RNAs or through miR polymorphism. As part of the inflammatory response, miRs control the expression of sets of related genes and have an enormous impact on the periodontal host response against periodontal pathogens and even affect gene expression within some of the pathogens, such as herpesvirus populations residing within the periodontal lesion.

Figure 2.. Inflammation-related microRNA expression in healthy and diseased gingiva and periodontal ligament, human gingival fibroblasts and PDL fibroblasts, human monocytes, and mouse RAW cells.

There was a significant upregulation or downregulation of select miRs (miR-100, miR-125a, miR-146a, and miR-155) in response to inflammatory conditions. * p <0.05, ** p < 0.01, *** p < 0.001. HG = healthy gingiva, DG = diseased gingiva, G-Con = human gingival fibroblast control, G-LPS = LPS treated gingival fibroblasts, HP = healthy periodontal ligament, DP = diseased periodontal ligament, P-Con = human PDL cells, P-LPS = LPS treated PDL cells, M-Con = human monocyte control, M-LPS = LPS treated human monocytes, R-Con = RAW264.7 murine monocyte/macrophage like cells, R-LPS = LPS treated RAW264.7 cells.