Periodontal Inflammation Primes the Systemic Innate Immune Response

Abstract

The presence of periodontal diseases (PDs) often strongly correlates with other severe chronic inflammatory conditions, including cardiovascular disease, diabetes, and arthritis. However, the mechanisms through which these diseases interact are unclear. In PD, tissue and bone destruction in the mouth is driven by elevated recruitment of polymorphonuclear neutrophils (PMNs), which are primed and recruited from the circulation to sites of inflammation. We predicted that systemic effects on PMN mobilization or priming could account for the interaction between PD and other inflammatory conditions. We tested this using a mouse model of ligature-induced PD and found elevated PMN counts specifically in bone marrow, supporting a systemic effect of periodontal tissue inflammation on PMN production. In contrast, mice with induced peritonitis had elevated PMN counts in the blood, peritoneum, and colon. These elevated counts were further significantly increased when acute peritonitis was induced after ligature-induced PD in mice, revealing a synergistic effect of multiple inflammatory events on PMN levels. Flow cytometric analysis of CD marker expression revealed enhanced priming of PMNs from mice with both PD and peritonitis compared to mice with peritonitis alone. Thus, systemic factors associated with PD produce hyperinflammatory PMN responses during a secondary infection. To analyze this systemic effect in humans, we induced gingival inflammation in volunteers and also found significantly increased activation of blood PMNs in response to ex vivo stimulation, which reverted to normal following resolution of gingivitis. Together, these results demonstrate that periodontal tissue inflammation has systemic effects that predispose toward an exacerbated innate immune response. This indicates that peripheral PMNs can respond synergistically to simultaneous and remote inflammatory triggers and therefore contribute to the interaction between PD and other inflammatory conditions. This suggests larger implications of PD beyond oral health and reveals potential new approaches for treating systemic inflammatory diseases that interact with PD.

Periodontal Health and Systemic Conditions

“…The role of the C-Reactive protein in this pathogenesis appears to be one that has strong evidence in its favor [ 14 , 15 ]. A recent study, which used ligature-induced periodontal disease in mouse models and human experimental gingivitis model, demonstrated that periodontal inflammation can result in increased polymorphonuclear neutrophils (PMNs) and potentially prime the systemic innate immune response [ 16 ]. This PMN-mediated hyperinflammatory innate immune response could be the plausible biologic crosslink between periodontal disease and the other chronic inflammatory diseases such as cardiovascular diseases, diabetes and arthritis.…”

Connection between Periodontitis-Induced Low-Grade Endotoxemia and Systemic Diseases: Neutrophils as Protagonists and Targets

“…A multitude of clinical findings demonstrated an unambiguous correlation between periodontitis and systemic diseases, like atherosclerosis, diabetes, and cardiovascular diseases [ 1 ]. The main link between systemic diseases and periodontitis is considered to be the systemic low-grade inflammation (SLGI); apparently a consequence of low-grade endoxemia (LGE) [ 2 , 3 , 4 , 5 , 6 , 7 ].…”

ZNF718, HOXA4, and ZFP57 are differentially methylated in periodontitis in comparison with periodontal health: Epigenome‐wide DNA methylation pilot study

“…1,2 An important mechanism in the progression of periodontal disease is the innate and adaptive inflammatory response after infection by periodontal pathogens. [3][4][5] There are important differences in susceptibility due to inter-individual genetic variants 6 ; for example, genetic variants of IL-37 can affect its expression and immunomodulatory response in relationship with periodontal disease. 7 Besides, a meta-analysis of genetic variations also found that a point mutation in CD14, an actor in innate immune response, is associated with some forms of periodontitis.…”