Impaired Immune Tolerance toPorphyromonas gingivalisLipopolysaccharide Promotes Neutrophil Migration and Decreased Apoptosis

Abstract

Periodontitis, a chronic inflammatory disease of the tissues supporting the teeth, is characterized by an exaggerated host immune and inflammatory response to periopathogenic bacteria. Toll-like receptor activation, cytokine network induction, and accumulation of neutrophils at the site of inflammation are important in the host defense against infection. At the same time, induction of immune tolerance and the clearance of neutrophils from the site of infection are essential in the control of the immune response, resolution of inflammation, and prevention of tissue destruction. Using a human monocytic cell line, we demonstrate that Porphyromonas gingivalis lipopolysaccharide (LPS), which is a major etiological factor in periodontal disease, induces only partial immune tolerance, with continued high production of interleukin-8 (IL-8) but diminished secretion of tumor necrosis factor alpha (TNF-␣) after repeated challenge. This cytokine response has functional consequences for other immune cells involved in the response to infection. Primary human neutrophils incubated with P. gingivalis LPS-treated naïve monocyte supernatant displayed a high migration index and increased apoptosis. In contrast, neutrophils treated with P. gingivalis LPS-tolerized monocyte supernatant showed a high migration index but significantly decreased apoptosis. Overall, these findings suggest that induction of an imbalanced immune tolerance in monocytes by P. gingivalis LPS, which favors continued secretion of IL-8 but decreased TNF-␣ production, may be associated with enhanced migration of neutrophils to the site of infection but also with decreased apoptosis and may play a role in the chronic inflammatory state seen in periodontal disease.

Polymicrobial Infection with Periodontal Pathogens Specifically Enhances MicroRNA miR-146a in ApoE −/− Mice during Experimental Periodontal Disease

“…Interestingly, the proinflammatory cytokine IL-8 was present at similar levels for all three HK bacterial stimulations and remained at higher levels for several hours. The potency of all three HK bacterial species alone or in combination with respect to cytokine excretion is consistent with data from previously reported studies (4, 40, (52). In their study, Escherichia coli LPS-tolerized THP-1 monocytes had reduced levels of IL-8 excretion with repeated LPS challenges, whereas P. gingivalis-tolerized monocytes did not.…”

“…Markedly, the stimulation of IL-1␤ secretion by P. gingivalis, T. denticola, and T. forsythia may be an important mechanism that amplifies the inflammatory response, the induction of connective tissue-degrading enzymes, and osteoclastic alveolar bone resorption (26). Furthermore, IL-8 as well as RANTES aid neutrophil, monocyte, and TH 1 cell recruitment to the site of infection (35,52). Previously, cytokine expression was observed for infection with HK P. gingivalis, T. denticola, and T. forsythia, but there has been no report on the effect of live bacterial infection on undifferentiated THP-1 monocytes (4,40).…”

Altered Toll-like Receptor 2-mediated Endotoxin Tolerance Is Related to Diminished Interferon β Production

“…We have already reported that impaired immune tolerance to P. gingivalis LPS is responsible for neutrophil-dominated chronic inflammation seen in periodontitis (25). In the current study we show that in contrast to E. coli LPS-induced tolerance, which is characterized by the down-regulation of human IL-8 and TNF-␣ and mouse KC, MIP-2, and TNF-␣ production, P. gingivalis LPS-pretreated human monocytes and mouse bone marrow-derived macrophages remained able to secret IL-8 and KC and MIP-2, respectively, but production of TNF-␣ was significantly decreased.…”

Functional characterization of Aggregatibacter actinomycetemcomitans QSEBC : a bacterial adrengeric receptor and global regulator of virulence.

“…Although macrophages have been shown to release higher amounts of catecholamines, infiltrating neutrophils are in a higher abundance during periodontitis [95,96] and are more likely to have an effect on periodontal microbes like A. actinomycetemcomitans due to their release of catecholamines. Therefore, a better understanding of how oral bacteria, specifically A.…”