# Angiotensin-Converting Enzyme 2 as a Possible Correlation between COVID-19 and Periodontal Disease
## 5 ACE2 and Periodontitis  
Recent studies have shown the presence of ACE2 and, consequently, of the RAS system in the oral cavity, mainly in cells associated with the periodontal structure [33]. Indeed, osteoblasts, osteoclasts, and fibroblasts are involved in the conservation of bone and soft tissues, which play a key role in maintaining and guaranteeing the stability and functionality of the teeth. As mentioned before, regulation of the inflammatory pattern by ACE2 might be connected to the response in periodontal disease (Figure 2).  
Figure 2: ACE2 levels and biofilm as enhancers in periodontal disease in periodontal and COVID-19 patients.  
Thus, the system formed with Ang1-7 and MasR has a positive effect on reducing cytokine levels in periodontal patients [34]. On the other hand, several factors can improve or impair the progression of the disease. The initiation pathway is completely different from that of SARS-CoV-2; indeed, bacteria are involved in facilitating the initiation of an inflammatory response inside the periodontal pocket. During a SARS-CoV-2 coinfection, the periodontal pattern might be exacerbated due to the downregulation of ACE2 and an increase in ACE and Ang II, with the consequent involvement of several pro-inflammatory factors. The cytokines involved are numerous: IL-6, IL-7, IL-2, TNF-\(\alpha\), IL-1\(\beta\), and MCP-1. IL-6 has a crucial role in the onset and acute phase of periodontal disease [35]. It is also associated with bone homeostasis. Indeed, the activation of Receptor activator of nuclear factor kappa-B ligand (RANKL)in osteoblasts might be upregulated by IL-6, leading to the activation of osteoclasts and bone resorption [36; 37]. Elevated IL-17 levels have been determined in the crevicular fluid of chronic periodontitis patients and correlated with disease severity [38; 39; 40]. IL-17 and a dysbiotic microbiome might promote each other, leading to the enhancement of both microbiome pathogenicity and mucosal immunopathology [40; 41]. TNF-\(\alpha\) is associated with bone metabolism, upregulating RANKL expression in gingival epithelial cells, T cells, and osteoblasts [42; 43]. TNF-\(\alpha\) also mediates the apoptosis of gingival fibroblasts and epithelial cells and inhibits extracellular matrix production in gingival fibroblasts [44], thus TNF-\(\alpha\) might be involved in the initiation of periodontitis by damaging the gingiva and the oral mucosa. IL-1\(\beta\) has been shown to induce the expansion and activation of both T helper 1 and T helper 2 cells as a result of the host-microbiota interaction [45]. MCP-1 is expressed as the predominant cytokine of gingival tissues and it has a main role in the chemotaxis of monocytes in inflamed tissues, enhancing the release of IL and TNFs [46; 47]. Thus, ACE2 can regulate cytokine expression through the Ang1-7 and MasR axis and this might have a fundamental role in all inflammatory diseases, such as periodontitis [33]. Downregulation of IL-6, TNF-\(\alpha\), IL-1\(\beta\), MCP-1, and IL-17 might improve the survival rate of hopeless teeth, reducing inflammation and consequently facilitating the healing phase.