Abstract
A finely-tuned innate immune response plays a pivotal role in protecting host against bacterial invasion during periodontal disease progression. Hyperlipidemia has been suggested to exacerbate periodontal health condition. However, the underlying mechanism has not been addressed. In the present study, we investigated the effect of hyperlipidemia on innate immune responses to periodontal pathogen Porphyromonas gingivalis infection. Apolipoprotein E-deficient and wild-type mice at the age of 20 weeks were used for the study. Peritoneal macrophages were isolated and subsequently used for the study of viable P. gingivalis infection. ApoE−/− mice demonstrated inhibited iNOS production and impaired clearance of P. gingivalis in vitro and in vivo; furthermore, ApoE−/− mice displayed disrupted cytokine production pattern in response to P. gingivalis, with a decreased production of tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β and monocyte chemotactic protein-1. Microarray data demonstrated that Toll-like receptor (TLR) and NOD-like receptor (NLR) pathway were altered in ApoE−/− mice macrophages; further analysis of pattern recognition receptors (PRRs) demonstrated that expression of triggering receptors on myeloid cells-1 (TREM-1), an amplifier of the TLR and NLR pathway, was decreased in ApoE−/− mice macrophages, leading to decreased recruitment of NF-κB onto the promoters of the TNF-α and IL-6. Our data suggest that in ApoE−/− mice hyperlipidemia disrupts the expression of PRRs, and cripples the host’s capability to generate sufficient innate immune response to P. gingivalis, which may facilitate immune evasion, subgingival colonization and establishment of P. gingivalis in the periodontal niche.
Highlights
Periodontal disease,a common infection-driven chronic inflammatory disease, is characterized by destruction of the supporting tissues around the tooth
We found that long term hyperlipidemia impaired the immune response to P. gingivalis challenge by altering pattern recognition receptors (PRRs) expression pattern in macrophages, leading an inhibited cytokine network response and decreased bacterial clearance; hyperlipidemia may lead to more severe periodontal bone loss
Based on antibiotic protection-based intracellular killing assay, we found that macrophages from hyperlipidemic ApoE2/2 mice showed a decreased tendency to internalize P. gingivalis after 1.5 h incubation (P.0.05), whereas intracellular capability to remove P. gingivalis was impaired in macrophages from ApoE2/ 2 mice in vitro
Summary
Periodontal disease,a common infection-driven chronic inflammatory disease, is characterized by destruction of the supporting tissues around the tooth. The innate immune system uses sentinel cells (monocytes, neutrophils, macrophages, dendritic cells), bearing pattern recognition receptors (PRRs), to recognize common molecular patterns on periodontal bacterial invaders, generating the immune and inflammatory responses, which leads to clearance of the bacteria [2]. Hyperlipidemia, resulting from impaired lipid metabolism by undue intake of cholesterol or genetic deficiency, has been suggested to exacerbate periodontal parameters in periodontitis patients in epidemiologic studies [3,4,5]. High-cholesterol food or fatty acid itself may depress immune function and bactericidal effect on P. gingivalis in the host [6,7], and feeding animals a highcholesterol diet impairs lipid metabolism and enhances periodontal destruction in lipopolysacchride (LPS) induced periodontitis in rats [8]. The underlying mechanism by which hyperlipidemia influences periodontal disease progress, especially the interaction between the innate immune system (including the PRRs) and the periodontal pathogen remains to be established
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