Periodontal innate immune mechanisms relevant to atherosclerosis and obesity

Abstract

Periodontal disease presents with a wide range of clinical variability and severity. Research in the past decade has shed substantial light on both the initiating infectious agents and host immunological responses in periodontal disease, both of which have been shown to modify the progression of periodontal disease. Cullinan et al. [28] have shown that up to 46% of the general population harbor the causative organism(s) of periodontal disease, but many are able to limit the progression of periodontal disease or even clear the organism(s) if infected. Overall, Cullinan et al. [28] suggest a complex multifactorial etiology of periodontal disease between host `immune' response and environmental factors. The characteristics of an individual's immune response to infectious agents greatly determine the severity of periodontal disease [119]. Michalowicz et al. [82] used a twin study to show that genetic hereditability appears to contribute approximately 50% to the clinical susceptibility of periodontal disease. In addition, studies have suggested dysregulation of innate immunity as playing a key role in progression of periodontal disease [110]. Specifically, the host immune response is suppressed upon low-level stimulation of critical pattern recognition receptors, leading to a muted local immune response, thus enabling periodontal disease-associated bacteria such as Porphyromonas gingivalis to evade host immune system [86, 114]. In the last decade, several epidemiological studies have also found an association between obesity and an increased incidence of periodontal disease [43, 101–104]. Recently, obesity has been shown to contribute to an individual's immune response to many pathogens such as P. gingivalis [43]. The effect of obesity on an individual's immune response was further characterized by Amar et al. [6], in showing reduced pro-inflammatory cytokine response, e.g. tumor necrosis factor-alpha, upon P. gingivalis infection in obese versus lean mice. Taken together, both obesity and chronic exposure to periodontal disease-associated bacteria, e.g. P. gingivalis, alone appear to mute the local immune response and in combination may synergize in suppressing the innate immune system, thus further exacerbating periodontal disease. Epidemiologic evidence has further suggested that the long-term effects of periodontal disease can be linked to more serious systemic conditions such as cardiovascular disease, diabetes, and complications of pregnancy [18, 24–25, 30–31, 90]. Bahekar et al. [12] determined a statistically significant increase in prevalence of coronary heart disease in patients with periodontitis between 1.14- to 1.59-fold increase after adjusting for risk factors such as smoking, diabetes, alcohol intake, obesity, and blood pressure. Recently, Amar et al. [5] have shown that the presence of a P. gingivalis bacteremia alone, a common complication in patients with periodontal disease, is not sufficient to exacerbate atherosclerosis; rather, bacteremia coupled with intra-cellular invasion of endothelial cells by P. gingivalis is required. Upon invasion, endothelial cells activate and upregulate various adhesion molecules, thus increasing the likelihood of macrophage diapedesis and, when coupled with exposure to a high fat diet, subsequent conversion to foam cells thus furthering athroma progression [32]. In addition, mature athroma macrophages display reduced responsiveness from their pattern recognition receptors, in a fashion similar to that seen in the response to low-level stimulation of lipopolysaccharides [86, 114]. Lipopolysaccharides induces a similar state of tolerance and dysregulation in endothelial cells and circulating white blood cells [37]. Taken together, both mechanisms further exacerbate the effect of periodontal disease on the progression of atherosclerosis. This review will focus on exploring the molecular mechanisms underlying host immune response(s) to P. gingivalis fostering periodontal disease, the exacerbating effects of obesity on periodontal disease, and the long-term accelerating effects that periodontal disease has on the progression of atherosclerosis. We suggest that innate immune tolerance is a common molecular mechanism linking periodontal disease, obesity and atherosclerosis in concert leaving an individual with a dysregulated and dysfunctional innate immune response, which is critical for enhancement of both periodontal disease and atherosclerosis. Overall, a picture is emerging that shows tolerance in the innate immune system occurring as a result of persistent low-level exposure to P. gingivalis infection or induced by obesity paralyses the innate immune response and further aggravates periodontal disease. As a consequence of enhanced periodontal disease an individual is subjected to repeated bacteremias with P. gingivalis, which can lead to both endothelial dysfunction and repeated bouts of inflammation. Both processes affect the endothelium by increasing the likelihood for macrophages to transit across the arterial intima and under hyperlipidemia / hypercholesterolemic conditions foster the conversion of macrophages into foam cells, therefore further exacerbating atherosclerosis. Thus, understanding the mechanisms of tolerance and its effect on innate immunity may contribute valuable insights into all three conditions: periodontal disease, obesity and atherosclerosis.