Abstract
The possible relationship between periodontal disease resulting from the infection of gingival tissue by the Gram-negative bacterium Porphyromonas gingivalis (P. gingivalis) and the development of neuroinflammation remains under investigation. Recently, P. gingivalis lipopolysaccharide (LPS) was reported in the human brain, thus suggesting it might activate brain microglia, a cell type participating in neuroinflammation. We tested the hypothesis of whether in vitro exposure to ultrapure P. gingivalis LPS may result in classical and alternative activation phenotypes of rat microglia, with the concomitant release of cytokines and chemokines, as well as superoxide anion (O2−), thromboxane B2 (TXB2), and matrix metalloprotease-9 (MMP-9). After an 18-h exposure of microglia to P. gingivalis LPS, the concentration-dependent responses were the following: 0.1–100 ng/mL P. gingivalis LPS increased O2− generation, with reduced inflammatory mediator generation; 1000–10,000 ng/mL P. gingivalis LPS generated MMP-9, macrophage inflammatory protein 1α (MIP-1α/CCL3), macrophage inflammatory protein-2 (MIP-2/CXCL2) release and significant O2− generation; 100,000 ng/mL P. gingivalis LPS sustained O2− production, maintained MMP-9, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) release, and triggered elevated levels of MIP-1α/CCL3, MIP-2/CXCL2, and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL-1), with a very low release of lactic dehydrogenase (LDH). Although P. gingivalis LPS was less potent than Escherichia coli (E. coli) LPS in stimulating TXB2, MMP-9, IL-6 and interleukin 10 (IL-10) generation, we observed that it appeared more efficacious in enhancing the release of O2−, TNF-α, MIP-1α/CCL3, MIP-2/CXCL2 and CINC-1/CXCL-1. Our results provide support to our research hypothesis because an 18-h in vitro stimulation with ultrapure P. gingivalis LPS resulted in the classical and alternative activation of rat brain microglia and the concomitant release of cytokines and chemokines.
Highlights
Periodontal disease is a multifactorial and common inflammatory condition in humans that may involve chronic infection of the gingival tissue by the Gram-negative bacteria P. gingivalis [1].When the infection is severe, as in periodontitis, it has been hypothesized as a risk factor for cognitive impairment and neuropathology, including dementia and Alzheimer’s disease [2,3,4]
Initial support for this hypothesis was recently provided by Ilievski et al, who observed, for the first time, that orally applied P. gingivalis translocated to murine brain, and was found in astrocytes, neurons and microglia, with the concomitant generation of inflammatory cytokines, and development of neurodegeneration [5]
P. gingivalis LPS has been detected in the human brains, raising the possibility that it might activate human brain microglia [6,7]
Summary
When the infection is severe, as in periodontitis, it has been hypothesized as a risk factor for cognitive impairment and neuropathology, including dementia and Alzheimer’s disease [2,3,4]. Initial support for this hypothesis was recently provided by Ilievski et al, who observed, for the first time, that orally applied P. gingivalis translocated to murine brain, and was found in astrocytes, neurons and microglia, with the concomitant generation of inflammatory cytokines, and development of neurodegeneration [5].
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