Oral inflammatory diseases and systemic inflammation: role of the macrophage

Abstract

Inflammation is a complex reaction to injurious agents and includes vascular responses, migration, and activation of leukocytes. Inflammation starts with an acute reaction, which evolves into a chronic phase if allowed to persist unresolved. Acute inflammation is a rapid process characterized by fluid exudation and emigration of leukocytes, primarily neutrophils, whereas chronic inflammation extends over a longer time and is associated with lymphocyte and macrophage infiltration, blood vessel proliferation, and fibrosis. Inflammation is terminated when the invader is eliminated, and the secreted mediators are removed; however, many factors modify the course and morphologic appearance as well as the termination pattern and duration of inflammation. Chronic inflammatory illnesses such as diabetes, arthritis, and heart disease are now seen as problems that might have an impact on the periodontium. Reciprocal effects of periodontal diseases are potential factors modifying severity in the progression of systemic inflammatory diseases. Macrophages are key cells for the inflammatory processes as regulators directing inflammation to chronic pathological changes or resolution with no damage or scar tissue formation. As such, macrophages are involved in a remarkably diverse array of homeostatic processes of vital importance to the host. In addition to their critical role in immunity, macrophages are also widely recognized as ubiquitous mediators of cellular turnover and maintenance of extracellular matrix homeostasis. In this review, our objective is to identify macrophage-mediated events central to the inflammatory basis of chronic diseases, with an emphasis on how control of macrophage function can be used to prevent or treat harmful outcomes linked to uncontrolled inflammation.

Keywords: inflammation; innate immune system; macrophage; oral disease; resolution.

Figure 1

Lipopolysaccharides (LPS) recognition and signaling in macrophages. CD14 and moesin are expressed on the cell membrane in macrophages. LPS stimulation results in phosphorylation of moesin, binding to the TLR4 and MD-2 activating the MyD88. Signaling through this mechanism leads to the production of pro-inflammatory cytokines (Zawawi et al., 2010).

Figure 2

Regulation of inflammation by resolvin-E1 in experimental periodontitis. (A) Periodontal disease was induced by ligature and Porphyromonas gingivalis application over 6 weeks in rabbits. Classical characteristic of periodontal disease including tissue and bone loss were observed. (B) Sites were treated either with RvE1 (1 mg/ml) or vehicle (ethanol) for an additional 6 weeks. RvE1 treatment did not only stop the disease progression but also reversed the tissue and bone loss and allowed the tissues to reach to a completely healthy state. Vehicle treatment did not have any impact on controlling the disease, conversely the disease continued to progress. (C) Histological evaluations confirmed the clinical observations where RvE1 treated sites showed no bone loss and no or minimal inflammatory cell activity. (D) Histomorphometric evaluations quantified the bone level changes during these treatments over 6 weeks. While RvE1 treatment resulted in bone gain, vehicle treatment showed worsening and lost more bone as a result of disease progression.

Figure 3

Local periodontal inflammation as a modifier of atherosclerotic changes in aortas of high cholesterol-fed rabbits. (A) Atherosclerosis was induced by high cholesterol diet (0.5%) in rabbits over 13 weeks. Simultaneously, periodontal disease was also induced as explained above over a 6-weeks period. At 13 weeks, the aortas dissected en face and stained with Sudan IV for detection of lipid depositions. As a result of high cholesterol diet, rabbits developed early fatty streaks as indicated by Sudan IV stained lipid depositions mainly limited at the aortic arch and thoracic aorta. Rabbits challenged with P. gingivalis showed dramatically more and extended level of lipid depositions covering almost entire surfaces of thoracic and abdominal aortas. (B) Quantification of lipid covered area clearly showed that local periodontal inflammation significantly increases the atherosclerotic changes induced by cholesterol diet. (C) Periodontal disease was also more dramatic in those rabbits received high cholesterol diet suggesting a reciprocal relationship between local and systemic inflammations. (D) The severity of bone loss was positively correlated with degree of the fatty streaks (lipid depositions; r² = 0.9501).

Figure 4

Lipoxin A₄, a resolution phase agonist, conferred similar actions with RvE1 on periodontal tissues challenged by P. gingivalis and ligature. (A) Periodontal inflammation was induced in transgenic and non-transgenic rabbits as described elsewhere for 6 weeks. Simultaneously, topical LXA₄ (5–6 μg/site) was applied to the ligated sites in some non-transgenic animals. At 6 weeks, similar to RvE1, Lipoxin A₄ resulted in significant reduction of tissue inflammation as a result of disease initiation. 15 LO overexpressing transgenic rabbits (15 LO-TG) exhibited no inflammation or tissue destruction and were completely protected from periodontal inflammatory changes. (B) The defleshed specimens clearly showed the amount of bone loss as a result of the periodontal disease induced by the human oral microorganism, P. gingivalis (left panel). LXA₄ was capable of preventing from these inflammatory changes and bone loss (middle panel), while the 15 LO-TG rabbits were not affected by disease induction, and were completely resistant to the disease (right panel). (C) Histological evaluations have confirmed the clinical observations and once again showed a complete protection in 15 LO-TG rabbits from inflammatory changes demonstrated by an unaffected healthy bony architecture (right panel). Topical LXA₄ application protected from the destructive effects of periodontal disease as indicated by histological evaluations (middle panel).